Bremelanotide

References

1. Available from https://www.wptv.com/news/national/fda-approves-new-drug-for-women-with-low-sexual-desire-disorder.
   View Summary +

   Bremelanotide: New Drug Approved for Treating Hypoactive Sexual Desire Disorder

   Bremelanotide, a newly approved therapy for hypoactive sexual desire disorder (HSDD), was
   reviewed through a literature search encompassing relevant studies from January 1996 to December
   2019. This search included phase 2 and 3 trials of bremelanotide, resulting in the inclusion of
   2 phase 3 and 2 phase 2 trial reports. The data synthesis revealed that bremelanotide
   significantly improves desire and reduces distress associated with the lack of desire in
   individuals with HSDD. Common adverse effects include nausea, facial flushing, and headache. As
   the second FDA-approved treatment for HSDD, bremelanotide’s exact place in therapy is uncertain
   due to outdated HSDD guidelines from 2017. While the trials demonstrated statistical
   significance in improving sexual desire and related distress, the actual clinical benefit might
   be modest. Bremelanotide is administered as a subcutaneous injection around 45 minutes before
   sexual activity, deemed safe with minimal drug interactions and no significant interactions with
   ethanol. Prescribing guidelines suggest a maximum of 1 dose within 24 hours and no more than 8
   doses per month. If no benefit is observed after 8 weeks, discontinuation is recommended.

   You can read the abstract at https://pubmed.ncbi.nlm.nih.gov/31893927/

2. Available from https://www.medscape.com/viewarticle/914779
3. Clayton AH, Althof SE, Kingsberg S, et al. Bremelanotide for Female Sexual Dysfunctions in Premenopausal
   Women: A Randomized, Placebo-Controlled Dose-Finding Trial. Women’s Health. 2016;12(3):325-337.
   doi:10.2217/whe-2016-0018.
   View Summary +

   Bremelanotide for Female Sexual Dysfunctions in Premenopausal Women: A Randomized,
   Placebo-Controlled Dose-Finding Trial
   The study aimed to assess the effectiveness and safety of bremelanotide (BMT), a
   melanocortin-receptor-4 agonist, in treating female sexual dysfunctions in premenopausal women.
   The patients were divided into groups receiving placebo or different doses of BMT (0.75, 1.25,
   or 1.75 mg) via self-administered subcutaneous injections over 12 weeks. The main measurement
   was the change in the frequency of satisfying sexual events per month. Secondary measurements
   included changes in scores on the female sexual function index and female sexual distress scale,
   particularly related to desire, arousal, and orgasm.

   The results showed that for the pooled 1.25 mg and 1.75 mg BMT doses compared to placebo, there
   were positive changes in the frequency of satisfying sexual events (+0.7 vs. +0.2 events/month),
   improvements in the female sexual function index total score (+3.6 vs. +1.9), and reductions in
   the female sexual distress scale scores related to desire, arousal, and orgasm (-11.1 vs. -6.8).
   Adverse events such as nausea, flushing, and headaches were reported.

   In conclusion, the study demonstrated that self-administered subcutaneous BMT was effective,
   safe, and well-tolerated in premenopausal women with female sexual dysfunctions. The trial’s
   registration number is NCT01382719.

   You can read the full article at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5384512/

4. Safarinejad MR. Evaluation of the safety and efficacy of bremelanotide, a melanocortin receptor agonist, in
   female subjects with arousal disorder: a double-blind placebo-controlled, fixed dose, randomized study. The
   journal of sexual medicine. 2008; 5(4):887-97.
   View Summary +

   Evaluation of the safety and efficacy of bremelanotide, a melanocortin receptor agonist,
   in female subjects with arousal disorder: a double-blind placebo-controlled, fixed dose,
   randomized study
   The article mentioned has been retracted as per the Elsevier Policy on Article Withdrawal. The
   retraction was initiated by the Editor-in-Chief of the journal. Following the retraction of Dr.
   Safarinejad’s previous work by other journals, The Journal of Sexual Medicine conducted a
   comprehensive re-review of all papers authored by Dr. Safarinejad that were published in their
   journal. After a thorough reassessment and careful examination of the manuscripts, expert
   reviewers identified multiple concerning issues related to the methodology, results, and
   statistical interpretation presented in this specific article.

   In an effort to address the raised concerns, Dr. Safarinejad was contacted to provide the
   original data and explanations. However, Dr. Safarinejad opted not to respond to these
   inquiries. Consequently, the journal is unable to verify the accuracy of the results and methods
   as presented in the article. As a result, the article has been retracted.

   You can read the abstract at https://pubmed.ncbi.nlm.nih.gov/18179455/

5. Diamond LE, Earle DC, Heiman JR, Rosen RC, Perelman MA, Harning R. An effect on the subjective sexual
   response in premenopausal women with sexual arousal disorder by bremelanotide (PT-141), a melanocortin
   receptor agonist. The journal of sexual medicine. 2006; 3(4):628-638.
   View Summary +

   An effect on the subjective sexual response in premenopausal women with sexual arousal
   disorder by bremelanotide (PT-141), a melanocortin receptor agonist
   Hypoactive sexual desire disorder (HSDD) is characterized by a persistent lack of sexual
   fantasies and desire, causing distress or difficulties in relationships. Symptoms include
   reduced interest in sexual activity, decreased response to sexual cues, loss of interest during
   sex, and avoidance of sexual situations. HSDD’s underlying causes involve hormonal,
   neurotransmitter, and brain anatomy factors. Its treatment is complex, aiming to address both
   biological and psychosocial aspects. Bremelanotide, a melanocortin receptor agonist, has gained
   FDA approval for HSDD treatment. Administered intranasally or as a subcutaneous injection, the
   recommended dose is 1.75 mg at least 45 minutes before sexual activity. Studies have
   demonstrated improved desire, arousal, and orgasm scores with this dosage compared to a placebo,
   making bremelanotide a promising option for HSDD treatment.

   You can read the full article at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8788464/

6. Allahdadi KJ, Tostes RCA, Webb RC. Female Sexual Dysfunction: Therapeutic Options and Experimental
   Challenges. Cardiovascular & hematological agents in medicinal chemistry. 2009;7(4):260-269.
   View Summary +

   You can read the full article at Female Sexual Dysfunction: Therapeutic Options and
   Experimental Challenges
   Female sexual dysfunction (FSD) affects around 40% of women and is more common as they age. It
   encompasses issues like vaginal dryness, pain during intercourse, reduced arousal, and
   difficulty reaching orgasm. Despite its prevalence, few treatment options exist, and only a
   minority of affected women seek medical help. Unlike the extensive research and treatment for male erectile dysfunction, FSD has received less attention and is mainly treated through psychological therapy. Cardiovascular diseases like atherosclerosis, peripheral arterial disease, and hypertension, often associated with aging and male erectile dysfunction, have also been linked to FSD. Animal studies have expanded our understanding, but more research is needed to effectively treat FSD. This review aims to provide up-to-date information on FSD, recent progress in understanding its underlying mechanisms, and emerging therapeutic possibilities. You can read the full article at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8788464/

7. Brown AD, Blagg J, Reynolds DS. Designing drugs for the treatment of female sexual dysfunction. Drug
   discovery today. 2007; 12(17-18):757-66.
   View Summary +

   Designing drugs for the treatment of female sexual dysfunction
   About 30% of women experience dysfunction in sexual desire, arousal, or achieving orgasm.
   Initial efforts to address female sexual dysfunction were adapted from treatments for male
   erectile dysfunction, but these attempts have had limited success. A new approach is emerging,
   focusing on targets that potentially influence central pathways involved in sexual function.
   Neurotransmitter systems like dopamine and serotonin, along with the neuropeptide melanocortin,
   are receiving considerable attention in this context. Preliminary clinical data are encouraging;
   however, clinical trial methodologies for female sexual dysfunction are not well-established.
   Further testing is necessary to determine whether these treatments can meet regulatory
   requirements and effectively address the needs of patients.

   You can read the full article at https://www.sciencedirect.com/science/article/abs/pii/S1359644607002759?via%3Dihub

8. Retrieved from https://www.palatin.com/research-focus/female-sexual-dysfunction/phase-3-reconnect-studies/
   View Summary +

   Female Sexual Dysfunction
   Female sexual dysfunction significantly impacts the quality of life for numerous women. In the
   United States, about 40% of women experience sexual issues, yet these complaints often go
   underrecognized and undertreated. The terminology and classification systems for female sexual
   dysfunction can be complex, hindering accurate clinical diagnosis. Treatment options for these
   dysfunctions are limited, though some interventions show potential benefits and are discussed.
   Ongoing research is exploring additional treatments. Establishing clear clinical categories and
   diagnostic guidelines for female sexual dysfunction is crucial, as it can greatly aid clinical
   practice, public health efforts, and research related to these conditions.

   You can read the full article at https://www.sciencedirect.com/science/article/abs/pii/S0025712519300112?via%3Dihub

9. Molinoff PB, Shadiack AM, Earle D, Diamond LE, Quon CY. PT-141: a melanocortin agonist for the treatment of
   sexual dysfunction. Annals of the New York Academy of Sciences. 2003; 994:96-102. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/12851303
   View Summary +

   PT-141: a melanocortin agonist for the treatment of sexual dysfunction
   PT-141 is a synthetic peptide similar to alpha-MSH that acts as an agonist at melanocortin
   receptors, particularly MC3R and MC4R, primarily located in the central nervous system. In
   experiments with rats and nonhuman primates, PT-141 induces penile erections. In rats, systemic
   PT-141 administration activates neurons in the hypothalamus, as evidenced by increased c-Fos
   immunoreactivity. Neurons in this brain region also demonstrate uptake of pseudorabies virus
   injected into the rat penis. When given to both healthy men and those with erectile dysfunction,
   PT-141 leads to a rapid, dose-dependent increase in erectile activity. These findings suggest
   that PT-141 could be a promising novel treatment for sexual dysfunction.

   You can read the abstract at https://nyaspubs.onlinelibrary.wiley.com/doi/abs/10.1111/j.1749-6632.2003.tb03167.x?sid=nlm%3Apubmed

10. Rosen RC, Diamond LE, Earle DC, Shadiack AM, Molinoff PB. Evaluation of the safety, pharmacokinetics and
    pharmacodynamic effects of subcutaneously administered PT-141, a melanocortin receptor agonist, in healthy
    male subjects and in patients with an inadequate response to Viagra. International journal of impotence
    research. 2004; 16(2):135-42
    View Summary +

    Evaluation of the safety, pharmacokinetics and pharmacodynamic effects of subcutaneously
    administered PT-141, a melanocortin receptor agonist, in healthy male subjects and in
    patients with an inadequate response to Viagra

    The study evaluated PT-141, a cyclic heptapeptide melanocortin analog, through subcutaneous
    administration in healthy males and patients with erectile dysfunction (ED) who had an
    inadequate response to Viagra. Inadequate response was defined as achieving suitable erections
    for vaginal penetration less than or equal to 50% of the time with 100 mg Viagra. Healthy
    subjects received doses from 0.3 to 10 mg, showing a significant erectile response at doses over
    1.0 mg. ED patients were given placebo, 4 mg, or 6 mg of PT-141 in a crossover design during
    visual sexual stimulation (VSS). Both PT-141 doses induced a statistically significant erectile
    response. The treatment was well tolerated and safe in both studies. PT-141’s potential to
    induce erections, its tolerability, and its efficacy in patients with inadequate responses to
    PDE5 inhibitors suggest it could offer an alternative ED treatment for a broad range of
    patients.

    You can read the abstract at https://www.nature.com/articles/3901200

11. Safarinejad MR, Hosseini SY. Salvage of sildenafil failures with bremelanotide: a randomized, double-blind,
    placebo controlled study. The Journal of urology. 2008; 179(3):1066-71.
    View Summary +

    Salvage of sildenafil failures with bremelanotide: a randomized, double-blind, placebo
    controlled study

    The study aimed to assess the safety and effectiveness of intranasal bremelanotide in men
    with erectile dysfunction (ED) who didn’t respond to sildenafil, a commonly used ED
    medication. The researchers conducted a randomized trial involving 342 married men aged 28
    to 59 years with ED. These men were divided into two groups: one receiving 10 mg
    bremelanotide as an intranasal spray before sexual activity, and the other receiving a
    placebo spray. Participants were required to use the treatment at least 16 times at home.
    They were evaluated using medical history, self-administered questionnaires, and assessment
    of various ED-related factors.

    The results showed that 33.5% of the men in the bremelanotide group experienced positive
    clinical outcomes, compared to only 8.5% in the placebo group. Additionally, the
    bremelanotide group reported higher satisfaction with sexual intercourse compared to the
    placebo group. However, there were more drug-related side effects in the bremelanotide
    group. The study concluded that bremelanotide could be a potential alternative treatment for
    ED in individuals who do not respond to sildenafil. However, further research is needed to
    determine the drug’s effectiveness at different dosages and treatment schedules.

    You can read the abstract at https://www.auajournals.org/doi/10.1016/j.juro.2007.10.063..

12. King SH, Mayorov AV, Balse-Srinivasan P, Hruby VJ, Vanderah TW, Wessells H. Melanocortin Receptors,
    Melanotropic Peptides and Penile Erection. Current topics in medicinal chemistry. 2007;7(11):1098-1106.
    View Summary +

    Melanocortin Receptors, Melanotropic Peptides and Penile Erection

    Penile erection is a complex process involving interactions between the nervous system and
    specialized vascular tissues. Activation of certain melanocortinergic (MC) receptors in the
    central nervous system (CNS) by natural or synthetic melanotropic ligands can trigger or
    facilitate spontaneous penile erection. The specific MC receptors involved, mainly MC3 and
    MC4 subtypes, have generated conflicting research regarding their roles in erection
    initiation. While MC4R seems to be the primary contributor to MC-induced erections, MC3R’s
    role remains less understood.

    Recent studies involving receptor-specific agonists, antagonists, and knockout mice have shed
    light on the distinct contributions of these receptor subtypes. Emerging research suggests
    that blocking MC3R in the forebrain might enhance melanocortin-induced erections.
    Additionally, melanocortin compounds might interact with established systems like
    oxytocinergic pathways at various CNS levels.

    Traditional treatments for erectile dysfunction focus on the vascular tissue of the genital
    area. Manipulating MC receptors presents an alternative approach, targeting central
    mechanisms for treating not only erectile dysfunction but also related sexual dysfunctions
    such as decreased sexual motivation and libido loss. The “superpotent” MC agonist PT-141,
    derived from MT-II, has progressed to phase II human trials. Melanocortin agonists show
    promise as centrally acting therapies, addressing both erectile dysfunction and broader
    sexual health concerns.

    You can read the full article at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2694735/

13. Shadiack AM, Sharma SD, Earle DC, Spana C, Hallam TJ. Melanocortins in the treatment of male and female
    sexual dysfunction. Curr Top Med Chem. 2007;7(11):1137-44.
    View Summary +

    Melanocortins in the treatment of male and female sexual dysfunction

    In the past two decades, research on male and female sexual responses has resulted in various
    pharmacological options for treating male erectile dysfunction (ED) and female arousal and
    orgasmic disorders. Some approaches target peripheral mechanisms like nitric oxide/cyclic
    GMP signaling, which affects genital vascular and nonvascular smooth muscles. Others
    consider central pathways involved in arousal, orgasmic functions in females, and induction
    of penile erection in males. Alongside dopaminergic agonists, drugs affecting the central
    melanocortin system are considered promising for addressing sexual dysfunctions in both
    genders.

    This review outlines progress in the clinical development of melanocortin receptor (MCR)
    agonists (melanotan I, melanotan II, bremelanotide) for treating sexual arousal and orgasmic
    disorders in adult females, as well as erectile dysfunction in males. The available data
    have enhanced our understanding of how the melanocortin pathway regulates male and female
    sexual functions. However, more research is needed to fully explore the effects of specific
    MCR agonists on penile erection and female arousal and orgasmic functions.

    You can read the abstract at https://www.tandfonline.com/doi/abs/10.1517/13543784.2014.934805?journalCode=ieid20

14. Diamond LE, et al. Co-administration of low doses of intranasal PT-141, a melanocortin receptor agonist, and
    sildenafil to men with erectile dysfunction results in an enhanced erectile response. Urology.
    2005;65(4):755–9.
    View Summary +

    Co-administration of low doses of intranasal PT-141, a melanocortin receptor agonist,
    and sildenafil to men with erectile dysfunction results in an enhanced erectile
    response

    The study aimed to assess the safety and effects of combining subtherapeutic doses of PT-141,
    a melanocortin analogue, with sildenafil in patients with erectile dysfunction. Nineteen
    patients, who responded to either Viagra or Levitra, underwent a randomized crossover design
    involving three different treatments: 25 mg sildenafil and 7.5 mg intranasal PT-141, 25 mg
    sildenafil and an intranasal placebo spray, and a placebo tablet and an intranasal placebo
    spray. Erectile responses were measured using RigiScan during a 6-hour period after
    treatment.

    The results demonstrated that co-administration of PT-141 and sildenafil led to a
    significantly greater erectile response compared to sildenafil alone. The combination
    treatment was found to be safe and well-tolerated, with no new adverse events or increased
    frequency/severity of adverse events compared to monotherapy. The findings suggest that
    combining intranasal PT-141 with a phosphodiesterase type 5 inhibitor like sildenafil could
    be a viable treatment option for patients who do not respond well to higher doses of a
    single therapy or have issues with tolerability.

    You can read the abstract at https://www.goldjournal.net/article/S0090-4295(04)01272-5/fulltext

15. Albersen M, Shindel A, Mwamukonda K, Lue T. The future is today: emerging drugs for the treatment of
    erectile dysfunction. Expert opinion on emerging drugs. 2010;15(3):467-480.
    doi:10.1517/14728214.2010.480973. Retrieved from //www.ncbi.nlm.nih.gov/pmc/articles/PMC3163612/.
    View Summary +

    The future is today: emerging drugs for the treatment of erectile dysfunction. Expert
    opinion on emerging drugs

    Erectile dysfunction (ED) is a prevalent male sexual issue affecting 10-20% of men, with
    phosphodiesterase type 5 inhibitors (PDE5Is) being the primary treatment. However, there’s a
    subset of ED patients not responding to PDE5Is. This review explores emerging compounds for
    ED treatment, focusing on both central (clavulanic acid, dopamine, and melanocortin receptor
    agonists) and peripheral (novel PDE5Is, guanylate cyclase activators, rho-kinase inhibitors,
    and maxi-K channel openers) regulation of penile erection.

    The review provides insights into the pathophysiology of erectile function, discussing
    mechanisms of action, effectiveness, and adverse effects of various compounds in development
    for ED treatment. The emerging drugs are expected to offer personalized treatment,
    considering each patient’s unique needs and balancing efficacy with potential side effects.
    Combination therapies involving these emerging drugs might be used to enhance effectiveness,
    particularly for challenging cases.

    You can read the full article at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3163612/

16. Koochaki, P., Revicki, D., Wilson, H., Pokrzywinski, R., Jordan, R., Lucas, J., Williams, L. A., Sadiq, A.,
    & Krop, J. (2021). The Patient Experience of Premenopausal Women Treated with Bremelanotide for Hypoactive
    Sexual Desire Disorder: RECONNECT Exit Study Results. Journal of women’s health (2002), 30(4), 587–595.
    https://doi.org/10.1089/jwh.2020.8460.
    View Summary +

    The Patient Experience of Premenopausal Women Treated with Bremelanotide for
    Hypoactive Sexual Desire Disorder: RECONNECT Exit Study Results

    Hypoactive sexual desire disorder (HSDD) significantly affects women’s well-being and
    relationships. The RECONNECT clinical trials revealed that bremelanotide led to substantial
    improvements in sexual desire and related distress in premenopausal women with HSDD,
    compared to placebo. Exit surveys and patient interviews were conducted to understand HSDD’s
    impact and bremelanotide’s effects from the patients’ viewpoint.

    After completing the double-blind study but before entering the open-label extension, around
    250 participants were invited to complete an exit survey (17 questions), and up to 90 were
    interviewed by phone (17 questions). Patient blinding to the study drug was maintained until
    surveys and interviews were finished.

    Survey results showed that women receiving bremelanotide experienced heightened sexual
    desire, physical arousal, and overall sexual quality in their relationships. In contrast,
    placebo recipients reported benefits that didn’t involve the physiological changes described
    by the bremelanotide group. Women on bremelanotide reported better communication with their
    sexual partner and positive experiences seeking treatment for HSDD.

    These exit surveys and interviews confirmed the primary RECONNECT trial findings and offered
    a comprehensive understanding of HSDD’s impact on quality of life and patients’ perceptions
    of bremelanotide’s effects.

    You can read the abstract at https://www.liebertpub.com/doi/10.1089/jwh.2020.8460?url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org&rfr_dat=cr_pub++0pubmed.

17. Kingsberg SA, Clayton AH, Portman D, Williams LA, Krop J, Jordan R, Lucas J, Simon JA. Bremelanotide for the
    Treatment of Hypoactive Sexual Desire Disorder: Two Randomized Phase 3 Trials. Obstet Gynecol. 2019
    Nov;134(5):899-908. doi: 10.1097/AOG.0000000000003500. PMID: 31599840; PMCID: PMC6819021.
    View Summary +

    Bremelanotide for the Treatment of Hypoactive Sexual Desire Disorder: Two Randomized
    Phase 3 Trials

    The study aimed to assess the safety and effectiveness of bremelanotide for treating
    hypoactive sexual desire disorder (HSDD) in premenopausal women

    Two identical phase 3 trials, collectively referred to as RECONNECT, were conducted. These
    were randomized, double-blind, placebo-controlled, multicenter trials. Premenopausal women
    with HSDD were randomized to receive either bremelanotide 1.75 mg subcutaneously or placebo
    for 24 weeks. The primary efficacy endpoints were changes in the Female Sexual Function
    Index-desire domain score and Female Sexual Distress Scale-Desire/Arousal/Orgasm item 13
    from baseline to the end of the study.

    The trials included 1,247 participants in the safety population and 1,202 participants in the
    efficacy population. Participants taking bremelanotide experienced statistically significant
    increases in sexual desire and reductions in distress related to low sexual desire compared
    to those on placebo. The most common side effects associated with bremelanotide were nausea,
    flushing, and headache. However, the majority of adverse events were mild or moderate in
    intensity.

    In conclusion, both studies demonstrated that bremelanotide significantly improved sexual
    desire and related distress in premenopausal women with HSDD. The treatment was generally
    well-tolerated, with the main adverse events being related to tolerability and mostly mild
    or moderate in nature.

    You can read the full article at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6819021/

18. Simon, J. A., Kingsberg, S. A., Portman, D., Williams, L. A., Krop, J., Jordan, R., Lucas, J., & Clayton, A.
    H. (2019). Long-Term Safety and Efficacy of Bremelanotide for Hypoactive Sexual Desire Disorder. Obstetrics
    and gynecology, 134(5), 909–917. https://doi.org/10.1097/AOG.0000000000003514.
    View Summary +

    Long-Term Safety and Efficacy of Bremelanotide for Hypoactive Sexual Desire Disorder
    

    The study aimed to assess the long-term safety and effectiveness of bremelanotide for
    treating hypoactive sexual desire disorder (HSDD) in premenopausal women.

    Participants who completed the 24-week double-blind core phase of the RECONNECT study, which
    consisted of two parallel phase 3 trials (301 and 302), could join a 52-week open-label
    extension. This extension evaluated the continuation of bremelanotide treatment for HSDD.
    Only those who did not experience serious adverse events during the core phase were eligible
    for the extension. Efficacy was measured using the same endpoints as in the core phase, and
    adverse events were monitored throughout the extension.

    The open-label extension began in 2015 and concluded in 2017. Of the eligible participants,
    684 out of 856 chose to participate in the extension, and 272 completed it. The most common
    treatment-related adverse events included nausea, flushing, and headache. Notably, no new
    safety issues emerged during the extension. Participants who received bremelanotide during
    the core phase and continued in the extension maintained improvements in HSDD symptoms, as
    measured by the Female Sexual Function Index-desire domain score and Female Sexual Distress
    Scale-Desire/Arousal/Orgasm item 13.

    In conclusion, the 52-week open-label extension of the RECONNECT study showed sustained
    benefits in HSDD symptoms for premenopausal women treated with bremelanotide. The
    treatment’s safety profile remained consistent over the extended period, with no new
    concerns arising.

    You can read the abstract of this article at https://pubmed.ncbi.nlm.nih.gov/31599847/.

19. Simon JA, Kingsberg SA, Portman D, Williams LA, Krop J, Jordan R, Lucas J, Clayton AH. Long-Term Safety and
    Efficacy of Bremelanotide for Hypoactive Sexual Desire Disorder. Obstet Gynecol. 2019 Nov;134(5):909-917.
    doi: 10.1097/AOG.0000000000003514. PMID: 31599847; PMCID: PMC6819023
    View Summary +

    Long-Term Safety and Efficacy of Bremelanotide for Hypoactive Sexual Desire
    Disorder

    The study aimed to assess the long-term safety and efficacy of bremelanotide as a treatment
    for hypoactive sexual desire disorder (HSDD) in premenopausal women.
    Women who completed the 24-week double-blind core phase of the RECONNECT study, which
    consisted of two parallel phase 3 trials (301 and 302) comparing bremelanotide with placebo
    in premenopausal women with HSDD, were eligible to participate in a 52-week open-label
    extension phase, provided they did not experience serious adverse events during the core
    phase. Efficacy was evaluated using the same primary endpoints as in the core phase, and
    adverse events were recorded during the extension. Statistical analyses were descriptive in
    nature.

    The open-label extension for study 301 took place from July 17, 2015, to July 13, 2017, and
    for study 302, it occurred from October 5, 2015, to June 29, 2017. Out of the 856 patients
    who completed the core phase, 684 chose to participate in the extension, with 272 completing
    it. The most commonly reported treatment-related adverse events were nausea (40.4%),
    flushing (20.6%), and headache (12.0%). Nausea was the only severe treatment-related adverse
    event experienced by multiple participants in both studies during the open-label extension.
    The change in Female Sexual Function Index-desire domain score and Female Sexual Distress
    Scale-Desire/Arousal/Orgasm item 13 from baseline to the end of the extension ranged from
    1.25 to 1.30 and -1.4 to -1.7, respectively, for patients who received bremelanotide during
    the core phase. For patients who received placebo during the core phase, the changes were
    0.70-0.77 and -0.9, respectively.

    In conclusion, the 52-week open-label extension of the RECONNECT study demonstrated sustained
    improvements in HSDD symptoms for premenopausal women treated with bremelanotide. No new
    safety concerns emerged during this extension period.

    You can read the full article at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6819023/.

20. Edinoff AN, Sanders NM, Lewis KB, Apgar TL, Cornett EM, Kaye AM, Kaye AD. Bremelanotide for Treatment of
    Female Hypoactive Sexual Desire. Neurol Int. 2022 Jan 4;14(1):75-88. doi: 10.3390/neurolint14010006. PMID:
    35076581; PMCID: PMC8788464.
    View Summary +

    Bremelanotide for Treatment of Female Hypoactive Sexual Desire

    Hypoactive sexual desire disorder (HSDD) is characterized by persistent lack of sexual
    fantasies and desire leading to distress or relationship difficulties. It includes
    diminished interest and responsiveness to sexual cues, avoidance of sexual situations, and
    reduced motivation for sexual activity. HSDD’s origin involves hormones, neurotransmitters,
    and brain structure. Due to its complexity, treatment should address both biological and
    psychological aspects.

    Bremelanotide, a melanocortin receptor agonist, has received FDA approval for HSDD treatment.
    Administered intranasally or subcutaneously, the recommended dosage is 1.75 mg injected into
    the abdomen or thigh at least 45 minutes before sexual activity. Clinical studies
    demonstrated improved desire, arousal, and orgasm scores compared to a placebo when 1.75 mg
    of bremelanotide was taken before sexual activity. This treatment offers promise for
    managing HSDD.

    You can read the full article at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8788464/

21. Kingsberg SA, Clayton AH, Portman D, Williams LA, Krop J, Jordan R, Lucas J, Simon JA. Bremelanotide for the
    Treatment of Hypoactive Sexual Desire Disorder: Two Randomized Phase 3 Trials. Obstet Gynecol. 2019
    Nov;134(5):899-908. doi: 10.1097/AOG.0000000000003500. PMID: 31599840; PMCID: PMC6819021
    View Summary +

    Bremelanotide for the Treatment of Hypoactive Sexual Desire Disorder: Two Randomized
    Phase 3 Trials

    The study aimed to assess the safety and efficacy of bremelanotide for treating hypoactive
    sexual desire disorder (HSDD) in premenopausal women.

    Two identical phase 3 trials, referred to as RECONNECT, were conducted as randomized,
    double-blind, placebo-controlled, multicenter trials. Premenopausal women with HSDD were
    given subcutaneous bremelanotide 1.75 mg or placebo as needed for 24 weeks. Key efficacy
    endpoints were changes in the Female Sexual Function Index-desire domain score and the
    Female Sexual Distress Scale-Desire/Arousal/Orgasm item 13.

    The trials were conducted between January 2015 and August 2016. Of the 1,267 women
    randomized, 1,247 and 1,202 were part of the safety and efficacy populations, respectively.
    Majority were white (85.6%), from the U.S. (96.6%), and had an average age of 39 years.
    Bremelanotide-treated women experienced statistically significant increases in sexual desire
    and significant reductions in distress related to low sexual desire compared to placebo.
    Adverse events such as nausea, flushing, and headache were more common in the bremelanotide
    group

    In conclusion, both studies demonstrated that bremelanotide significantly improved sexual
    desire and related distress in premenopausal women with HSDD. The treatment was generally
    well-tolerated, with most adverse events being related to tolerability and mild or moderate
    in intensity.

    You can read the full article at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6819021/

22. Kingsberg, S. A., Clayton, A. H., Portman, D., Williams, L. A., Krop, J., Jordan, R., Lucas, J., & Simon, J.
    A. (2019). Bremelanotide for the Treatment of Hypoactive Sexual Desire Disorder: Two Randomized Phase 3
    Trials. Obstetrics and gynecology, 134(5), 899–908. https://doi.org/10.1097/AOG.0000000000003500
    View Summary +

    Bremelanotide for the Treatment of Hypoactive Sexual Desire Disorder: Two Randomized
    Phase 3 Trials

    The study aimed to assess the safety and efficacy of bremelanotide for treating hypoactive
    sexual desire disorder (HSDD) in premenopausal women

    Two identical phase 3 trials, referred to as RECONNECT, were conducted as randomized,
    double-blind, placebo-controlled, multicenter trials. Premenopausal women with HSDD were
    given subcutaneous bremelanotide 1.75 mg or placebo as needed for 24 weeks. Key efficacy
    endpoints were changes in the Female Sexual Function Index-desire domain score and the
    Female Sexual Distress Scale-Desire/Arousal/Orgasm item 13.

    The trials were conducted between January 2015 and August 2016. Of the 1,267 women
    randomized, 1,247 and 1,202 were part of the safety and efficacy populations, respectively.
    Majority were white (85.6%), from the U.S. (96.6%), and had an average age of 39 years.
    Bremelanotide-treated women experienced statistically significant increases in sexual desire
    and significant reductions in distress related to low sexual desire compared to placebo.
    Adverse events such as nausea, flushing, and headache were more common in the bremelanotide
    group

    In conclusion, both studies demonstrated that bremelanotide significantly improved sexual
    desire and related distress in premenopausal women with HSDD. The treatment was generally
    well-tolerated, with most adverse events being related to tolerability and mild or moderate
    in intensity.

    You can read the full article at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6819021/

23. Pfaus, J. G., Sadiq, A., Spana, C., & Clayton, A. H. (2022). The neurobiology of bremelanotide for the
    treatment of hypoactive sexual desire disorder in premenopausal women. CNS spectrums, 27(3), 281–289.
    https://doi.org/10.1017/S109285292100002X
    View Summary +

    The neurobiology of bremelanotide for the treatment of hypoactive sexual desire
    disorder in premenopausal women

    Hypoactive sexual desire disorder (HSDD) is a prevalent female sexual dysfunction, impacting
    around 10% of U.S. women. This disorder is linked to imbalances in brain hormone and
    neurotransmitter levels, causing reduced excitation, increased inhibition, or a combination
    of both. Neurotransmitters like dopamine, norepinephrine, serotonin, and hormones like
    estradiol and testosterone play roles in female sexual desire and response. Current HSDD
    treatments encompass psychotherapy, flibanserin (a serotonin mixed agonist/antagonist), and
    bremelanotide (a melanocortin receptor agonist) – both FDA-approved for premenopausal women.

    Bremelanotide activates melanocortin receptors (MCRs), neuropeptides associated with the
    excitatory pathway of the female sexual response system. The most relevant subtype is MC4R,
    situated primarily in the medial preoptic area (mPOA) of the hypothalamus. This region is
    pivotal for female sexual function. Bremelanotide’s mechanism of action involves activating
    presynaptic MC4Rs on mPOA neurons, leading to increased dopamine release – an excitatory
    neurotransmitter associated with heightened sexual desire.

    In summary, this review delves into bremelanotide’s mechanism of action within the context of
    treating HSDD. It highlights how bremelanotide’s activation of MC4Rs in the hypothalamus can
    potentially enhance sexual desire by boosting dopamine release.

    You can read the abstract at https://www.cambridge.org/core/journals/cns-spectrums/article/abs/neurobiology-of-bremelanotide-for-the-treatment-of-hypoactive-sexual-desire-disorder-in-premenopausal-women/CB2718A94BC8F52E562867A0F1689B15.

24. Kingsberg, S. A., Clayton, A. H., Portman, D., Williams, L. A., Krop, J., Jordan, R., Lucas, J., & Simon, J.
    A. (2019). Bremelanotide for the Treatment of Hypoactive Sexual Desire Disorder: Two Randomized Phase 3
    Trials. Obstetrics and gynecology, 134(5), 899–908. https://doi.org/10.1097/AOG.0000000000003500
    View Summary +

    Bremelanotide for the Treatment of Hypoactive Sexual Desire Disorder: Two Randomized
    Phase 3 Trials

    The study aimed to assess the safety and efficacy of bremelanotide for treating hypoactive
    sexual desire disorder (HSDD) in premenopausal women

    Two identical phase 3 trials, referred to as RECONNECT, were conducted as randomized,
    double-blind, placebo-controlled, multicenter trials. Premenopausal women with HSDD were
    given subcutaneous bremelanotide 1.75 mg or placebo as needed for 24 weeks. Key efficacy
    endpoints were changes in the Female Sexual Function Index-desire domain score and the
    Female Sexual Distress Scale-Desire/Arousal/Orgasm item 13.

    The trials were conducted between January 2015 and August 2016. Of the 1,267 women
    randomized, 1,247 and 1,202 were part of the safety and efficacy populations, respectively.
    Majority were white (85.6%), from the U.S. (96.6%), and had an average age of 39 years.
    Bremelanotide-treated women experienced statistically significant increases in sexual desire
    and significant reductions in distress related to low sexual desire compared to placebo.
    Adverse events such as nausea, flushing, and headache were more common in the bremelanotide
    group.

    In conclusion, both studies demonstrated that bremelanotide significantly improved sexual
    desire and related distress in premenopausal women with HSDD. The treatment was generally
    well-tolerated, with most adverse events being related to tolerability and mild or moderate
    in intensity

    You can read the full article at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6819021/.>

25. Koochaki, P., Revicki, D., Wilson, H., Pokrzywinski, R., Jordan, R., Lucas, J., Williams, L. A., Sadiq, A.,
    & Krop, J. (2021). The Patient Experience of Premenopausal Women Treated with Bremelanotide for Hypoactive
    Sexual Desire Disorder: RECONNECT Exit Study Results. Journal of women’s health (2002), 30(4), 587–595.
    https://doi.org/10.1089/jwh.2020.8460
    View Summary +

    The Patient Experience of Premenopausal Women Treated with Bremelanotide for
    Hypoactive Sexual Desire Disorder: RECONNECT Exit Study Results

    Hypoactive sexual desire disorder (HSDD) has a negative impact on women’s overall health and
    relationships. Primary analysis from the RECONNECT trials showed significant improvements in
    sexual desire and related distress with bremelanotide compared to placebo in premenopausal
    women with HSDD. To gauge patient perspectives, exit surveys and interviews were conducted
    after the double-blind phase but before the open-label extension.

    Around 250 participants completed quantitative exit surveys, and 80 of them also participated
    in qualitative telephone interviews. Participants receiving bremelanotide reported increased
    sexual desire, physical arousal, and improved overall sexual quality in their relationships.
    In contrast, placebo recipients didn’t report similar physiological responses but
    highlighted positive experiences seeking HSDD treatment and enhanced communication with
    partners

    In conclusion, exit surveys and interviews corroborate the primary RECONNECT findings,
    offering both quantitative and qualitative insights into how HSDD affects patients’ quality
    of life and their perspectives on bremelanotide’s impact

    You can read the abstract at https://www.liebertpub.com/doi/10.1089/jwh.2020.8460?url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org&rfr_dat=cr_pub++0pubmed>

26. Simon, J. A., Kingsberg, S. A., Portman, D., Jordan, R., Lucas, J., Sadiq, A., Krop, J., & Clayton, A. H.
    (2022). Prespecified and Integrated Subgroup Analyses from the RECONNECT Phase 3 Studies of Bremelanotide.
    Journal of women’s health (2002), 31(3), 391–400. https://doi.org/10.1089/jwh.2021.0225
    View Summary +

    Prespecified and Integrated Subgroup Analyses from the RECONNECT Phase 3 Studies of
    Bremelanotide

    Hypoactive sexual desire disorder (HSDD) is a common female sexual dysfunction characterized
    by reduced desire for sexual activity and distress. Bremelanotide, a melanocortin receptor
    agonist approved by the FDA for acquired generalized HSDD in premenopausal women, was
    investigated for its efficacy compared to placebo across various subgroups in the phase 3
    RECONNECT studies

    Patients self-administered bremelanotide or placebo before sexual activity for 24 weeks.
    Efficacy was assessed using changes in Female Sexual Function Index desire domain and Female
    Sexual Distress Scale-Desire/Arousal/Orgasm Item 13. Among the 1,202 patients in the
    integrated and subgroup analyses, bremelanotide yielded significant improvements in desire
    and decreased distress related to low desire in age, weight, BMI, and bioavailable
    testosterone subgroups. These improvements were consistent, with only a few exceptions

    Bremelanotide also led to increased reported sexual desire in patients not using hormonal
    contraceptives, with a numerical advantage observed in those using contraceptives.
    Regardless of contraceptive use, bremelanotide reduced distress significantly. The treatment
    achieved improvements in desire and distress irrespective of decreased arousal, HSDD
    duration, and across various subgroups

    In conclusion, bremelanotide demonstrated significant improvements in sexual desire and
    reduced distress in patients with HSDD across multiple predefined subgroups, with only a few
    exceptions.

    You can read the abstract at https://www.liebertpub.com/doi/10.1089/jwh.2021.0225?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed>

27. Diamond, L. E., Earle, D. C., Heiman, J. R., Rosen, R. C., Perelman, M. A., & Harning, R. (2006). An effect
    on the subjective sexual response in premenopausal women with sexual arousal disorder by bremelanotide
    (PT-141), a melanocortin receptor agonist. The journal of sexual medicine, 3(4), 628–638.
    https://doi.org/10.1111/j.1743-6109.2006.00268.x.
    View Summary +

    An effect on the subjective sexual response in premenopausal women with sexual
    arousal disorder by bremelanotide (PT-141), a melanocortin receptor agonist

    The study aimed to assess the effects of a single intranasal dose of bremelanotide on
    physiological and subjective measures of sexual arousal and desire in premenopausal women
    with sexual arousal disorder.

    Bremelanotide is a synthetic peptide melanocortin analog that acts as an agonist at
    melanocortin receptors MC3R and MC4R, which are associated with various physiological
    responses, including sexual behaviors.

    Eighteen premenopausal women with sexual arousal disorder participated in a double-blind
    study where they received a single intranasal dose of 20 mg bremelanotide or a matching
    placebo. Participants viewed neutral and sexually explicit videos while vaginal pulse
    amplitude was monitored using photoplethysmography. Questionnaires evaluated perceptions of
    sexual response within 24 hours after treatment.

    Results showed that more women reported moderate or high sexual desire following
    bremelanotide treatment compared to placebo. There was also a trend towards more positive
    responses regarding feelings of genital arousal after bremelanotide. Among women attempting
    sexual intercourse within 24 hours, more were satisfied with their level of sexual arousal
    following bremelanotide compared to placebo. However, vaginal vasocongestion did not
    significantly change during viewing erotic videos after bremelanotide administration
    compared to placebo. In conclusion, this preliminary study suggests that bremelanotide might
    positively impact desire and arousal in women with sexual arousal disorder, making it a
    promising candidate for further investigation in at-home studies.

    You can read the full article at https://academic.oup.com/jsm/article-abstract/3/4/628/6882956?redirectedFrom=fulltext&login=false.

28. Wessells, H., Hruby, V. J., Hackett, J., Han, G., Balse-Srinivasan, P., & Vanderah, T. W. (2003).
    Ac-Nle-c[Asp-His-DPhe-Arg-Trp-Lys]-NH2 induces penile erection via brain and spinal melanocortin receptors.
    Neuroscience, 118(3), 755–762. https://doi.org/10.1016/s0306-4522(02)00866-7.
    View Summary +

    Ac-Nle-c[Asp-His-DPhe-Arg-Trp-Lys]-NH2 induces penile erection via brain and spinal
    melanocortin receptors

    The study aimed to investigate the effects of melanocortin peptides on penile erection and
    yawning in male rats. The researchers administered the melanocortin receptor agonist MT-II
    through various routes (intracerebroventricular, intrathecal, and intravenous) and observed
    its impact. They also used the antagonist SHU-9119 to distinguish between spinal and
    supraspinal effects. The researchers found that MT-II induced dose-dependent penile
    erections, with yawning observed for certain administration routes. Spinal delivery of MT-II
    was more effective in inducing erections than other routes. The study confirmed that MT-II
    has central proerectile effects and identified melanocortin receptors in the spinal cord
    that can trigger erections independently of higher brain centers. These findings offer new
    insights into the pathways involved in penile erection and could potentially lead to
    improved for erectile dysfunction.

    You can read the abstract at https://www.ibroneuroscience.org/article/S0306-4522(02)00866-7/fulltext.

29. Kievit P, Halem H, Marks DL. Chronic treatment with a melanocortin-4 receptor agonist causes weight loss,
    reduces insulin resistance, and improves cardiovascular function in diet-induced obese rhesus macaques.
    Diabetes. 2013; 62(2):490-7
    View Summary +

    Chronic treatment with a melanocortin-4 receptor agonist causes weight loss, reduces
    insulin resistance, and improves cardiovascular function in diet-induced obese rhesus
    macaques

    The melanocortin-4 receptor (MC4R) plays a significant role in regulating body weight.
    Activation of MC4R leads to weight loss in rodents and is linked to obesity in humans. This
    makes MC4R a potential target for obesity treatment. However, previous studies have shown
    that MC4R agonists can cause various side effects, including increased heart rate and blood
    pressure. In this research, a new and highly selective MC4R agonist (BIM-22493 or RM-493)
    was tested on obese nonhuman primates. Treatment with this agonist led to short-term reduced
    food intake (35%) and sustained weight loss (13.5%) over 8 weeks. The treated animals also
    showed improved glucose tolerance and reduced fat accumulation. Importantly, there were no
    temporary increase in blood pressure or heart rate with this new agonist. In contrast,
    another MC4R agonist (LY2112688) that had previously caused high blood pressure and heart rate in
    humans did so again in this study, along with a modest decrease in food intake. This
    research highlights that different melanocortin peptide drugs can have varying levels of
    effectiveness and side effects.

    You can read the full article at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3554387/..

30. Emmerson PJ, Fisher MJ, Yan LZ, Mayer JP. Melanocortin-4 receptor agonists for the treatment of obesity.
    Current topics in medicinal chemistry. 2007; 7(11):1121-30.
    View Summary +

    Melanocortin-4 receptor agonists for the treatment of obesity

    The melanocortin receptor family (MC1-5R) and their natural peptide ligands (alpha, beta,
    gamma-MSH, and ACTH) play a role in various behavioral and physiological functions,
    including the regulation of food intake and body weight. Studies using rodent models have
    demonstrated that melanocortin agonists like MTII reduce food intake and body weight, while
    antagonists like SHU9119 and AGRP increase food intake and body weight. Deletion of MC3R or
    MC4R in mice leads to obesity, with hyperphagia observed mainly in MC4R-deficient mice.
    Similarly, in humans, inactivating mutations of MC4R are found in a portion of obese
    individuals. This suggests that MC4R activation might reduce food intake in humans,
    prompting the search for selective agonists for obesity treatment.

    Efforts to develop MC4R-selective small molecule and peptide agonists have seen limited
    success over the past decade. Some small molecule agonists have been identified, but few
    have shown in vivo activity. However, several potent and selective peptide agonists have
    been shown by various researchers to decrease food intake and body weight in rodent models.
    This review focuses on assessing the progress in creating small molecule and peptide MC4R
    agonists as potential therapies for obesity.

    You can read the abstract at https://www.eurekaselect.com/article/23386..

31. Jonsson L, Skarphedinsson JO, Skuladottir GV. Melanocortin receptor agonist transiently increases oxygen
    consumption in rats. Neuroreport. 2001; 12(17):3703-8
    View Summary +

    Melanocortin receptor agonist transiently increases oxygen consumption in
    rats

    The melanocortin receptor family (MC1-5R) and their natural peptide ligands (alpha, beta,
    gamma-MSH, and ACTH) play a role in various behavioral and physiological functions,
    including the regulation of food intake and body weight. Studies using rodent models have
    demonstrated that melanocortin agonists like MTII reduce food intake and body weight, while
    antagonists like SHU9119 and AGRP increase food intake and body weight. Deletion of MC3R or
    MC4R in mice leads to obesity, with hyperphagia observed mainly in MC4R-deficient mice.
    Similarly, in humans, inactivating mutations of MC4R are found in a portion of obese
    individuals. This suggests that MC4R activation might reduce food intake in humans,
    prompting the search for selective agonists for obesity treatment.

    Efforts to develop MC4R-selective small molecule and peptide agonists have seen limited
    success over the past decade. Some small molecule agonists have been identified, but few
    have shown in vivo activity. However, several potent and selective peptide agonists have
    been shown by various researchers to decrease food intake and body weight in rodent models.
    This review focuses on assessing the progress in creating small molecule and peptide MC4R
    agonists as potential therapies for obesity.

    You can read the abstract at https://journals.lww.com/neuroreport/abstract/2001/12040/melanocortin_receptor_agonist_transiently.20.aspx

32. Retrieved from https://docs.google.com/viewer?url=patentimages.storage.googleapis.com/pdfs/US20050101535.pdf
    View Summary +

33. Spana, C., Jordan, R., & Fischkoff, S. (2022). Effect of bremelanotide on body weight of obese women: Data
    from two phase 1 randomized controlled trials. Diabetes, obesity & metabolism, 24(6), 1084–1093.
    https://doi.org/10.1111/dom.14672
    View Summary +

    Effect of bremelanotide on body weight of obese women: Data from two phase 1
    randomized controlled trials

    The study aims to investigate the effects of bremelanotide, an agonist of the melanocortin 4
    receptor (MC4R), on appetite regulation, caloric intake, and body weight in premenopausal
    obese women. Two randomized controlled clinical trials were conducted

    In Study A, premenopausal women were either given subcutaneous placebo or bremelanotide three
    times daily for 15 days. The bremelanotide group exhibited a significant reduction in body
    weight (-1.3 kg) and a decrease in caloric intake (around 400 kcal/day) compared to the
    placebo group.

    Study B involved a crossover design with different treatment sequences, including once-a-day
    and twice-a-day exposure to bremelanotide versus placebo. Subjects receiving twice-daily
    bremelanotide showed a substantial reduction in body weight (1.7 kg) and a greater decrease
    in caloric intake (398-469 kcal) compared to the placebo group. Overall, these trials
    indicate that bremelanotide’s agonistic activity at MC4R appears to effectively reduce
    caloric intake and promote weight loss in obese premenopausal women

    You can read the full article at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9314948/.

34. Heisler LK, Cowley MA, Kishi T. Central serotonin and melanocortin pathways regulating energy homeostasis.
    Annals of the New York Academy of Sciences. 2003; 994:169-74
    View Summary +

    Central serotonin and melanocortin pathways regulating energy homeostasis

    The study focuses on understanding how the interaction between the central serotonergic
    (5-HT) system and the melanocortin systems within the hypothalamus affects energy balance
    and food intake regulation. The hypothalamus plays a crucial role in coordinating responses
    to changes in energy availability. Recent research has investigated how serotonin-related
    drugs influence pathways related to leptin responsiveness in the hypothalamus.

    Through a combination of functional neuroanatomy, feeding experiments, and electrophysiology
    studies in rodents, the researchers discovered that anorectic 5-HT drugs require functional
    melanocortin pathways to affect food intake. These drugs activate pro-opiomelanocortin
    (POMC) neurons in the arcuate nucleus of the hypothalamus. The study suggests that the
    serotonin 2C receptor (5-HT(2C)R) is expressed on POMC neurons and contributes to this
    effect. Moreover, the researchers found that the anorectic effects of 5-HT drugs are
    diminished when downstream melanocortin 3 and 4 receptors are blocked either
    pharmacologically or genetically.

    The study proposes a model in which the activation of the melanocortin system follows the
    activation of the 5-HT system and is essential for the complete anorectic effects of 5-HT
    drugs. This research integrates the central 5-HT system into the broader network of
    metabolic signals that converge on melanocortin neurons in the hypothalamus to regulate
    energy balance and food intake.

    You can read the abstract at https://nyaspubs.onlinelibrary.wiley.com/doi/abs/10.1111/j.1749-6632.2003.tb03177.x?sid=nlm%3Apubmed.

35. Lindblom J, Opmane B, Mutulis F. The MC4 receptor mediates alpha-MSH induced release of nucleus accumbens
    dopamine. Neuroreport. 2001; 12(10):2155-8
    View Summary +

    The MC4 receptor mediates alpha-MSH induced release of nucleus accumbens
    dopamine

    There is compelling evidence of a functional connection between the melanocortin and dopamine
    systems. The grooming behavior induced by alpha-Melanocyte Stimulating Hormone (alpha-MSH)
    appears to be linked to heightened dopaminergic activity in the striatal regions. This
    connection, which can be inhibited by dopamine receptor antagonists, hasn’t been
    definitively attributed to melanocortin (MC) receptors until now.

    Through microdialysis studies on anesthetized rats, researchers administered alpha-MSH into
    the ventral tegmental area. This led to a notable increase in dopamine and DOPAC (a dopamine
    metabolite) levels in the nucleus accumbens. Importantly, this rise in dopamine was entirely
    blocked when the MC4 receptor-specific antagonist HS131 was administered beforehand. This
    suggests that the influence of alpha-MSH on dopamine transmission is likely mediated through
    the MC4 receptor.

    You can read the abstract at
    https://journals.lww.com/neuroreport/abstract/2001/07200/the_mc4_receptor_mediates___msh_induced_release_of.22.aspx.

36. Lu XY, Barsh GS, Akil H, Watson SJ. Interaction between alpha-melanocyte-stimulating hormone and
    corticotropin-releasing hormone in the regulation of feeding and hypothalamo-pituitary-adrenal responses.
    The Journal of neuroscience : the official journal of the Society for Neuroscience. 2003; 23(21):7863-72
    View Summary +

    Interaction between alpha-melanocyte-stimulating hormone and corticotropin-releasing
    hormone in the regulation of feeding and hypothalamo-pituitary-adrenal
    responses

    Both alpha-melanocyte-stimulating hormone and corticotropin-releasing hormone (CRH) play
    roles in feeding and neuroendocrine processes. The similarity in function and anatomical
    distribution between these neurotransmitter systems raised the idea that CRH might be
    involved in mediating the central effects of the melanocortin system.

    Using double-labeling in situ hybridization, researchers identified that a subset of CRH
    neurons in the paraventricular nucleus of the hypothalamus (PVN) contains the melanocortin-4
    receptor (MC4R), primarily in the ventromedial region of the parvicellular PVN (up to 33%).
    Injecting the melanocortin agonist MTII into conscious rats led to rapid CRH gene
    transcription induction in the PVN. This was accompanied by a dose- and time-dependent
    increase in plasma corticosterone levels, peaking 30 minutes after MTII injection. The rise
    in plasma corticosterone triggered by MTII was reduced by the MC4R antagonist HS014 and the
    CRH receptor antagonist alpha-helical-CRH9-41, both in a dose-dependent manner.

    Furthermore, the study evaluated the anorectic effect of MTII on food intake at different
    time points after injection. The inhibitory impact of MTII on food intake was partly
    reversed by pretreatment with alpha-helical-CRH9-41. Collectively, these findings provide
    evidence that CRH operates as a downstream mediator of melanocortin signaling, contributing
    to how the central melanocortin system regulates feeding and neuroendocrine responses.

    You can read the full article at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6740604/.

37. Sabatier N, Caquineau C, Dayanithi G. Alpha-melanocyte-stimulating hormone stimulates oxytocin release from
    the dendrites of hypothalamic neurons while inhibiting oxytocin release from their terminals in the
    neurohypophysis. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2003;
    23(32):10351-8
    View Summary +

    Alpha-melanocyte-stimulating hormone stimulates oxytocin release from the dendrites
    of hypothalamic neurons while inhibiting oxytocin release from their terminals in the
    neurohypophysis

    Both the peptides alpha-melanocyte-stimulating hormone (alpha-MSH) and oxytocin produce
    similar behavioral effects when administered centrally. This study aimed to explore the
    relationship between alpha-MSH and oxytocin in terms of their effects on neuronal activity
    and the release of oxytocin.

    The study found that alpha-MSH induces the expression of Fos (a marker of neuronal
    activation) in the supraoptic nucleus when administered centrally or locally by
    retrodialysis. However, this increase in Fos expression does not correlate with an increase
    in the electrophysiological excitation of oxytocin neurons in the supraoptic nucleus. In
    fact, central injection of alpha-MSH or specific melanocortin-4 receptor (MC4R) agonists
    inhibited the electrical activity of oxytocin neurons recorded in vivo. This was supported
    by a decrease in oxytocin secretion into the bloodstream after central alpha-MSH injection.

    Interestingly, MC4R ligands, including alpha-MSH, induced significant oxytocin release from
    dendrites in isolated supraoptic nuclei. This dendritic oxytocin release appears to be
    triggered by changes in intracellular calcium concentration ([Ca2+]i). The study observed
    that MC4R ligands induce a transient increase in [Ca2+]i in oxytocin neurons, which could be
    due to the mobilization of calcium from intracellular stores rather than entry through
    voltage-gated channels.

    In summary, this research reveals that alpha-MSH can lead to differential regulation of
    dendritic release and systemic secretion of oxytocin. While alpha-MSH induces Fos
    expression, it inhibits the electrical activity of oxytocin neurons. However, MC4R ligands
    stimulate oxytocin release from dendrites through intracellular calcium mobilization. This
    study highlights the complex interplay between these peptides in regulating oxytocin-related
    processes.

    You can read the full article at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6741015/.

38. Modi ME, Inoue K, Barrett CE, et al. Melanocortin Receptor Agonists Facilitate Oxytocin-Dependent Partner
    Preference Formation in the Prairie Vole. Neuropsychopharmacology. 2015;40(8):1856-1865.
    doi:10.1038/npp.2015.35
    View Summary +

    Melanocortin Receptor Agonists Facilitate Oxytocin-Dependent Partner Preference
    Formation in the Prairie Vole

    The central melanocortin (MC) system, particularly the MC4 receptor (MC4R), interacts with
    neurochemical systems that regulate socioemotional behaviors, including oxytocin (OT) and
    dopamine. In monogamous prairie voles, OT and dopamine work together to promote partner
    preference formation, a measure of lasting social bonding between mates. This study aimed to
    explore how MC receptor activation influences partner preference formation in prairie voles
    and the interaction between the MC and OT systems during this process.

    Administering the MC3/4R receptor peptide agonist Melanotan II (MTII) and the selective MC4R
    agonist Pf-446687 peripherally enhanced partner preference formation in prairie voles, but
    not in non-monogamous meadow voles. The partner preferences induced by MTII were enduring,
    persisting even a week after drug treatment. The study suggests that the prosocial effects
    of MC receptor agonists might involve modulation of the OT system, as coadministration of an
    OT receptor antagonist prevented MTII-induced partner preferences.

    Furthermore, MTII selectively activated hypothalamic OT neurons and boosted central OT
    release. As OT is known to enhance certain aspects of social cognition in humans, the
    findings imply that MC4R could potentially be a therapeutic target for enhancing social
    function in psychiatric disorders like autism spectrum disorders and schizophrenia, possibly
    through the activation of the OT system.

    You can read the full article at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4839509/.

39. Barrett CE, Modi ME, Zhang BC, Walum H, Inoue K, Young LJ. Neonatal melanocortin receptor agonist treatment
    reduces play fighting and promotes adult attachment in prairie voles in a sex-dependent manner.
    Neuropharmacology. 2014; 85:357-66.
    View Summary +

    Neonatal melanocortin receptor agonist treatment reduces play fighting and promotes
    adult attachment in prairie voles in a sex-dependent manner

    The study focuses on the impact of the melanocortin receptor (MCR) system, known for its
    involvement in feeding and sexual behavior, on social behavior, which has been less
    explored. Specifically, the study examines the long-term effects of early-life MCR
    stimulation on social development in prairie voles.

    Researchers administered the MC3/4R agonist melanotan-II (MTII) to neonatal male and female
    prairie voles between postnatal days 1 and 7. The study found that male voles treated with
    MTII during this period showed reduced initiation of play fighting bouts as juveniles
    compared to control males. Neonatal exposure to MTII facilitated the formation of partner
    preferences in adult females but not males after a brief cohabitation with an opposite-sex
    partner.

    Additionally, acute injections of MTII triggered significant immediate early gene EGR-1
    immunoreactivity in hypothalamic oxytocin, vasopressin, and corticotropin-releasing factor
    neurons in neonatal animals. Daily neonatal treatment with a more selective MC4R agonist,
    PF44687, led to the development of partner preferences in both adult females and males. In
    conclusion, early-life exposure to MCR agonists resulted in persistent changes in social
    behavior in prairie voles, suggesting potential structural or functional alterations in the
    neural circuits involved in forming social relationships. The study highlights the complex
    role of the MCR system in regulating social behavior beyond its better-studied effects on
    feeding and sexual behavior.

    You can read the full article at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4158739/

40. Liu Y, Wang ZX. Nucleus accumbens oxytocin and dopamine interact to regulate pair bond formation in female
    prairie voles. Neuroscience. 2003; 121(3):537-44.
    View Summary +

    Nucleus accumbens oxytocin and dopamine interact to regulate pair bond formation in
    female prairie voles

    The study investigates the interactions between oxytocin (OT) and dopamine (DA) systems in
    pair bond formation in monogamous prairie voles. While both OT and DA have been linked to
    pair bonding, the precise nature of their interactions and the brain circuits involved
    remain unexplored.

    The study reveals that both OT and DA D2-type receptors are crucial for pair bond formation.
    Blocking either type of receptor prevents partner preferences induced by either OT or a
    D2-type agonist. The nucleus accumbens (NAcc) is identified as a key brain region for these
    interactions. In the NAcc, blocking OT receptors hinders the partner preferences induced by
    a D2-type agonist, while blocking D2-type DA receptors (but not D1-type receptors) hampers
    OT-induced partner preferences.

    In summary, the study concludes that the simultaneous activation of OT and DA D2-type
    receptors in the nucleus accumbens is essential for the formation of pair bonds in female
    prairie voles. This highlights the intricate interplay between these neurochemical systems
    and specific brain regions in regulating pair bonding behaviors.

    You can read the abstract at https://www.ibroneuroscience.org/article/S0306-4522(03)00555-4/fulltext.

41. Ross HE, Young LJ. Oxytocin and the neural mechanisms regulating social cognition and affiliative behavior.
    Frontiers in neuroendocrinology. 2009; 30(4):534-47
    View Summary +

    Oxytocin and the neural mechanisms regulating social cognition and affiliative
    behavior

    Oxytocin, produced in the hypothalamus and released through the neurohypophyseal system, has
    dual roles: peripheral release aids in childbirth and milk ejection, while central release
    coordinates maternal nurturing and mother-infant bonding. Recent research highlights
    oxytocin’s broader impact on affiliative behavior in both sexes. It influences alloparental
    care and pair bonding in female monogamous prairie voles and social recognition in male and
    female mice. In humans, oxytocin enhances social behaviors like increased eye gaze towards
    faces, interpersonal trust, and the ability to interpret emotions from facial expressions.
    Although the neurohypophyseal oxytocin system is well understood, less is known about
    oxytocin release within the brain. This review explores oxytocin’s role in regulating
    prosocial interactions and delves into the neuroanatomy of the central oxytocin system.

    You can read the full article at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2748133/.

42. Modi ME, Young LJ. D-cycloserine facilitates socially reinforced learning in an animal model relevant to
    autism spectrum disorders. Biological psychiatry. 2011; 70(3):298-304.
    View Summary +

    D-cycloserine facilitates socially reinforced learning in an animal model relevant to
    autism spectrum disorders

    Currently, there are no drugs that specifically address the social challenges of autism
    spectrum disorders (ASD). This gap could be attributed to a lack of relevant animal models
    and behavioral paradigms for ASD. Partner preference formation in prairie voles represents a
    form of socially reinforced learning, making it a valuable model for investigating social
    cognitive processes. D-cycloserine (DCS), a cognitive enhancer acting on
    N-methyl-D-aspartate receptors, is known to promote learning. The study aimed to explore
    whether DCS could enhance socially reinforced learning in the partner preference paradigm,
    potentially aiding social functioning in ASD when combined with behavioral therapies.

    Female prairie and meadow voles received either peripheral or direct brain region injections
    of DCS, including the nucleus accumbens (linked to reinforcement learning) and the amygdala
    (associated with social information processing). After cohabiting with a male vole under
    non-preference-inducing conditions, the development of a preference for the stimulus male
    vole over a novel one was measured through a partner preference test.

    Results indicated that a low dose of peripheral DCS enhanced partner preference formation in
    prairie voles, but not meadow voles, in situations where it wouldn’t naturally occur. This
    effect was reproduced in prairie voles using direct microinfusions of DCS into the nucleus
    accumbens and amygdala. In conclusion, partner preference formation in prairie voles offers
    a relevant behavioral paradigm for identifying pharmacotherapeutics addressing social
    deficits. The study suggests that DCS, when combined with social behavioral therapy, could
    be a potential treatment strategy for the social challenges associated with ASD

    You can read the full article at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3164818/

43. Toda C, Shiuchi T, Lee S, et al. Distinct Effects of Leptin and a Melanocortin Receptor Agonist Injected
    Into Medial Hypothalamic Nuclei on Glucose Uptake in Peripheral Tissues. Diabetes. 2009;58(12):2757-2765.
    doi:10.2337/db09-0638
    View Summary +

    Distinct Effects of Leptin and a Melanocortin Receptor Agonist Injected Into Medial
    Hypothalamic Nuclei on Glucose Uptake in Peripheral Tissues

    The study aimed to determine the contributions of the leptin receptor and melanocortin
    receptors (MCRs) in different medial hypothalamic nuclei to the regulation of peripheral
    glucose uptake. Leptin, a hormone influencing various physiological processes, was injected
    into specific medial hypothalamic nuclei in mice, and its effects on glucose uptake in
    peripheral tissues were observed. Additionally, an MCR agonist, MT-II, was also administered
    to examine its impact on glucose uptake.

    Results showed that injecting leptin into the ventromedial hypothalamus (VMH) increased
    glucose uptake in skeletal muscle, brown adipose tissue (BAT), and the heart. Leptin
    injection into the arcuate nucleus (ARC) enhanced glucose uptake in BAT, while injections
    into the dorsomedial hypothalamus (DMH) and paraventricular hypothalamus (PVH) had no effect
    on glucose uptake. The MCR antagonist SHU9119 blocked the effects of leptin in the VMH.

    Administering MT-II into the VMH or intracerebroventricularly increased glucose uptake in
    skeletal muscle, BAT, and the heart, while MT-II injection into the PVH increased glucose
    uptake in BAT. However, MT-II injections into the DMH or ARC did not influence glucose
    uptake.

    Conclusions drawn from the study indicate that the VMH plays a role in mediating glucose
    uptake in response to both leptin and MT-II in skeletal muscle, BAT, and the heart. These
    effects were dependent on MCR activation. The leptin receptor in the ARC and MCR in the PVH,
    on the other hand, were found to regulate glucose uptake in BAT. Overall, different medial
    hypothalamic nuclei have distinct roles in mediating glucose uptake in response to leptin
    and MT-II in peripheral tissues.

    You can read the full article at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2780865/

44. Kumar KG, Sutton GM, Dong JZ. Analysis of the therapeutic functions of novel melanocortin receptor agonists
    in MC3R- and MC4R-deficient C57BL/6J mice. Peptides. 2009; 30(10):1892-900
    View Summary +

    Analysis of the therapeutic functions of novel melanocortin receptor agonists in
    MC3R- and MC4R-deficient C57BL/6J mice

    The study focuses on novel non-selective melanocortin receptor agonists (BIM-22493,
    BIM-22511) that can cross the blood-brain barrier when administered peripherally. The
    effects of these agonists on obesity, insulin sensitivity, and liver metabolism were
    investigated in diet-induced obese mice.

    When administered peripherally, these melanocortin agonists improved obesity,
    hyperinsulinemia, and fatty liver disease in obese mice. The specificity of their function
    was confirmed using mice lacking melanocortin-3 receptor (MC3RKO) and melanocortin-4
    receptor (MC4RKO). Obesity, hyperinsulinemia, and hepatosteatosis were observed in MC4RKO
    mice, but not MC3RKO mice. The improvement in obesity and metabolic parameters associated
    with acute BIM-22493 treatment and 14 days of BIM-22511 treatment required functional MC4R,
    while MC3R was not essential.

    Chronic treatment with BIM-22511 reduced fasting insulin levels even in MC4RKO mice,
    demonstrating that the improvement in hyperinsulinemia is partially independent of MC4R.
    However, this treatment did not fully resolve hepatosteatosis in MC4RKO mice or influence
    hepatic lipogenic gene expression. In summary, peripherally administered melanocortin
    receptor agonists exert effects on body weight, liver metabolism, and glucose homeostasis
    through distinct pathways. MC4R is crucial for the agonist-induced weight loss and
    improvements in liver metabolism, while improvements in hyperinsulinemia can involve other
    melanocortin receptors. The study suggests that agonists targeting various melanocortin
    receptors could have potential for addressing glucose homeostasis abnormalities linked to
    obesity.

    You can read the full article at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2755620/

45. Zhou L, Sutton GM, Rochford JJ, et al. Serotonin 2C Receptor Agonists Improve Type 2 Diabetes via
    Melanocortin-4 Receptor Signaling Pathways. Cell Metabolism. 2007;6(5):398-405.
    doi:10.1016/j.cmet.2007.10.008.
    View Summary +

    Serotonin 2C Receptor Agonists Improve Type 2 Diabetes via Melanocortin-4 Receptor
    Signaling Pathways

    The increasing burden of type 2 diabetes and its associated health issues necessitates new
    and effective treatments. This study reveals that serotonin 2C receptor (5-HT(2C)R)
    agonists, known for their appetite-suppressing effects, significantly enhance glucose
    tolerance and reduce plasma insulin levels in murine models of obesity and type 2 diabetes.
    Importantly, these glucose-improving effects were observed at doses that did not impact
    eating behavior, energy expenditure, activity levels, body weight, or fat mass. The study
    further shows that the beneficial effects on glucose homeostasis are dependent on the
    activation of downstream melanocortin-4 receptors (MC4Rs), but not MC3Rs. This suggests that
    targeting 5-HT(2C)Rs pharmacologically might provide a novel approach to improving glucose
    tolerance in type 2 diabetes independently of weight-related changes.

    You can read the full article at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2075535/

46. Leckstrom A, Lew PS, Poritsanos NJ, Mizuno TM. Central melanocortin receptor agonist reduces hepatic
    lipogenic gene expression in streptozotocin-induced diabetic mice. Life sciences. 2011; 88(15-16):664-9
    View Summary +

    Central melanocortin receptor agonist reduces hepatic lipogenic gene expression in
    streptozotocin-induced diabetic mice

    The study aimed to investigate whether the central melanocortin system plays a role in
    regulating hepatic lipogenic gene expression under insulin-deficient conditions. Using a
    mouse model of insulin-deficient diabetes induced by streptozotocin (STZ), the researchers
    administered the melanocortin agonist MTII intracerebroventricularly (i.c.v.) to the
    diabetic mice. The effects of MTII treatment on hepatic gene expression were examined.

    Results showed that MTII treatment reduced the expression levels of genes involved in lipid
    biosynthesis, including stearoyl-CoA desaturase 1 (SCD1), glycerol-3-phosphate
    acyltransferase 1 (GPAT1), acyl-CoA:diacylglycerol acyltransferase 1 (DGAT1), and DGAT2,
    without affecting insulin levels, insulin resistance, or glucose tolerance. MTII treatment
    also decreased the protein levels of fatty acid synthase (FAS) and SCD1 in the liver.
    Additionally, the expression levels of transcription factors associated with these lipogenic
    genes, sterol regulatory element-binding protein 1c (SREBP-1c) and peroxisome
    proliferator-activated receptor γ2 (PPARγ2), were reduced by MTII treatment.

    These findings suggest that central melanocortin signaling can regulate hepatic lipogenic
    gene expression independently of insulin levels. Enhancing central melanocortin signaling
    might offer a potential approach to addressing abnormal lipid metabolism associated with
    insulin deficiency or insufficiency.

    You can read the abstract at https://www.sciencedirect.com/science/article/abs/pii/S0024320511000622?via%3Dihub

47. Retrieved from http://www.ingentaconnect.com/content/ben/ctmc/2007/00000007/00000011/art00008.
    View Summary +

48. Hall JE, Hildebrandt DA, Kuo J. Obesity hypertension: role of leptin and sympathetic nervous system.
    American journal of hypertension. 2001; 14(6 Pt 2):103S-115S
    View Summary +

    Obesity hypertension: role of leptin and sympathetic nervous system

    besity is strongly linked to essential hypertension, with excess renal sodium reabsorption
    and increased sympathetic activity playing key roles. Leptin, a hormone involved in appetite
    regulation, may partially connect obesity and heightened sympathetic activity. Studies
    indicate that leptin can increase renal sympathetic activity and elevate blood pressure and
    heart rate through adrenergic activation. Leptin’s effects on blood pressure may involve
    interactions with neurochemical pathways in the hypothalamus, including melanocortin-4
    receptors. However, the exact mechanisms by which leptin influences blood pressure, whether through these
    pathways or others like neuropeptide Y, remain uncertain. Leptin has additional actions,
    including promoting nitric oxide formation and improving insulin sensitivity, which could
    mitigate blood pressure effects in certain conditions. Given the growing obesity epidemic,
    further research is needed to fully understand these complex interactions and their
    relevance to human obesity-related hypertension.

    You can read the full article at https://academic.oup.com/ajh/article/14/S3/103S/205038?login=false

49. Nogueiras R, Wiedmer P, Perez-Tilve D, et al. The central melanocortin system directly controls peripheral
    lipid metabolism. The Journal of Clinical Investigation. 2007;117(11):3475-3488. doi:10.1172/JCI31743.
    View Summary +

    The central melanocortin system directly controls peripheral lipid metabolism

    Disruptions in the central nervous melanocortin system (CNS-Mcr) have been linked to obesity. Researchers investigated the role of this system in adiposity control, independent of nutrient intake. Inhibiting melanocortin receptors (Mcr) in rats and disrupting the Mc4r gene in mice led to increased lipid uptake, triglyceride synthesis, and fat accumulation in white adipose tissue (WAT). Conversely, enhanced CNS-Mcr signaling triggered lipid mobilization. These effects were not tied to food intake and occurred before changes in adiposity. Reduced CNS-Mcr signaling also improved insulin sensitivity and glucose uptake in WAT while decreasing glucose utilization in muscle and brown adipose tissue. These changes were linked to the sympathetic nervous system and liver triglyceride synthesis. These findings explain how decreased melanocortin signaling promotes adiposity even without increased eating and demonstrates its influence on substrate utilization. The study also reveals the molecular mechanisms underlying CNS-Mcr control over lipid metabolism, offering insights for designing more effective methods to manage adiposity.

    You can read the full article at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1978426/

50. VObici S, Feng Z, Tan J, Liu L, Karkanias G, Rossetti L. Central melanocortin receptors regulate insulin action. Journal of Clinical Investigation. 2001;108(7):1079-1085
    View Summary +

    Central melanocortin receptors regulate insulin action

    Leptin regulates energy balance and insulin action through the melanocortin pathway in the hypothalamus. This study investigated the impact of manipulating the melanocortin pathway on insulin action and adiposity distribution. Rats were infused with a melanocortin receptor agonist (alpha-MSH) or antagonist (SHU9119) while maintaining constant food intake. Alpha-MSH reduced intra-abdominal fat and significantly enhanced insulin’s effects on glucose uptake and production. In contrast, SHU9119 had opposite effects. These findings reveal a neuroendocrine network that plays a crucial role in connecting energy intake with insulin action.

    You can read the full article at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC200952/.

51. Maisto R, Gesualdo C, Trotta MC. Melanocortin receptor agonists MCR1-5 protect photoreceptors from high-glucose damage and restore antioxidant enzymes in primary retinal cell culture. Journal of cellular and molecular medicine. 2017; 21(5):968-974.
    View Summary +

    Melanocortin receptor agonists MCR1-5 protect photoreceptors from high-glucose damage and restore antioxidant enzymes in primary retinal cell culture

    Melanocortin receptors, particularly subtypes 1 and 5, play a protective role in diabetic retinopathy, a condition where retinal photoreceptors are vulnerable to high glucose levels and oxidative stress. This study investigated the effects of these receptors in primary retinal cell cultures exposed to high glucose concentrations. Treatment with agonists for melanocortin receptors 1 and 5 reduced inflammation and enhanced antioxidant enzyme levels, helping to preserve photoreceptor integrity. These findings suggest that these receptors have a significant role in safeguarding primary retinal cells from damage caused by high glucose or oxidative stress.

    You can read the full article at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5387132/

52. Rossi S, Maisto R, Gesualdo C, et al. Activation of melanocortin receptors MC1 and MC5 attenuates retinal damage in experimental diabetic retinopathy. Mediators Inflamm. 2016; 7368389
    View Summary +

    Activation of melanocortin receptors MC1 and MC5 attenuates retinal damage in experimental diabetic retinopathy

    In a mouse model of streptozotocin-induced diabetic retinopathy (DR), the study aimed to investigate the potential protective effects of melanocortin receptors (MC). About 80% of the diabetic mice developed microvascular changes resembling DR without vascular leakage. Occludin, a protein important for maintaining blood-retinal barrier integrity, decreased in these mice. Expression of MC receptors Mc1r and Mc5r was observed in the retina. Intravitreal injection of selective MC1 and MC5 agonists resulted in significant protection, maintaining regular retinal vessel structure. Diabetic mice had elevated levels of inflammatory and angiogenic factors in the retina, while MC agonists reversed these changes. MC3-MC4 agonist/antagonists did not affect the assessed parameters. These findings suggest that MC receptors, particularly MC1 and MC5, could activate protective mechanisms against DR-related changes in the retina.

    You can read the full article at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4753692/

53. Wolf Horrell EM, Boulanger MC, D’Orazio JA. Melanocortin 1 receptor: structure, function, and regulation. Front Genet. 2016; 7: 95.
    View Summary +

    Melanocortin 1 receptor: structure, function, and regulation

    The melanocortin 1 receptor (MC1R) is a Gs protein-coupled receptor with a pivotal role in regulating skin pigmentation, UV responses, and melanoma risk. It is highly polymorphic, and its loss of function leads to fair skin, UV sensitivity, and higher melanoma susceptibility due to impaired skin pigmentation and DNA repair. MC1R signaling involves adenylyl cyclase activation, generating cAMP as a second messenger. Hormonally controlled by melanocortin, agouti signaling protein, and β-defensin 3, cAMP signaling via MC1R increases melanin production and deposition in the skin’s epidermis. This melanin helps shield against UV penetration and enhances nucleotide excision repair (NER), a genomic stability mechanism that eliminates UV-induced DNA damage to prevent mutagenesis. This review outlines MC1R’s structure, function, and its influence on NER pathways.

    You can read the full article at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4885833/

54. Olney JJ, Sprow GM, Navarro M, Thiele TE. The protective effects of the melanocortin receptor (MCR) agonist, melanotan-II (MTII), against binge-like ethanol drinking are facilitated by deletion of the MC3 receptor in mice. Neuropeptides. 2014;48(1):47-51. doi:10.1016/j.npep.2013.11.001
    View Summary +

    The protective effects of the melanocortin receptor (MCR) agonist, melanotan-II (MTII), against binge-like ethanol drinking are facilitated by deletion of the MC3 receptor in mice

    Recent studies have linked the melanocortin (MC) system to the modulation of voluntary ethanol consumption. Melanotan-II (MTII), a nonselective melanocortin receptor (MCR) agonist, has been shown to reduce voluntary ethanol consumption in mice. Prior research indicated that central administration of MTII reduces ethanol drinking through the MC4R receptor, as observed in mice lacking MC4R expression. However, the neurocircuitry involved in binge-like ethanol drinking differs from moderate consumption. This study aimed to explore the role of MC3R in binge-like ethanol intake using the “drinking in the dark” (DID) procedure, a model for binge-like drinking. MC3R+/+ and MC3R-/- mice were given MTII intracerebroventricularly before a 4-hour ethanol access period. MTII reduced binge-like ethanol drinking in both types of mice, with MC3R-/- mice showing increased sensitivity to the protective effects of MTII. These findings suggest that MC3Rs counteract the protective effects of MTII against binge-like ethanol consumption, implying potential therapeutic use of selective MC3R antagonists in addressing excessive ethanol intake.

    You can read the full article at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3946855/

55. Navarro M, Carvajal F, Lerma-Cabrera JM, Cubero I, Picker MJ, Thiele TE. Evidence that Melanocortin Receptor Agonist Melanotan-II Synergistically Augments the Ability of Naltrexone to Blunt Binge-Like Ethanol Intake in Male C57BL/6J Mice. Alcoholism, clinical and experimental research. 2015;39(8):1425-1433. doi:10.1111/acer.12774.
    View Summary +

    Evidence that Melanocortin Receptor Agonist Melanotan-II Synergistically Augments the Ability of Naltrexone to Blunt Binge-Like Ethanol Intake in Male C57BL/6J Mice

    The study investigates the potential synergy between the melanocortin (MC) receptor agonist melanotan-II (MTII) and the opioid receptor antagonist naltrexone (NAL) in reducing binge-like alcohol (ethanol) consumption in mice. The authors explore the interaction between the MC and opioid systems, both of which modulate behaviors like pain, drug tolerance, and food intake. Using a mouse model of binge drinking, they find that both NAL and MTII independently reduce binge-like ethanol intake and blood ethanol levels. Interestingly, when administered together, a low dose of MTII significantly enhances the effectiveness of NAL in reducing binge-like ethanol consumption, leading to a synergistic effect. These findings suggest that targeting MC signaling, possibly in combination with opioid antagonism, could offer a novel strategy for treating alcohol abuse disorders and enhancing existing naltrexone-based therapies.

    You can read the full article at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4515169/

56. Navarro M, Cubero I, Chen AS, et al. Effects of Melanocortin Receptor Activation and Blockade on Ethanol Intake: A Possible Role for the Melanocortin-4 Receptor. Alcoholism, clinical and experimental research. 2005;29(6):949-957. doi:10.1097/01.ALC.0000167740.19702.8C
    View Summary +

    Effects of Melanocortin Receptor Activation and Blockade on Ethanol Intake: A Possible Role for the Melanocortin-4 Receptor

    The study examines the role of melanocortin receptors (MCRs) in modulating ethanol consumption. The researchers investigate the effects of MCR agonists and antagonists on alcohol intake in mice with different genetic backgrounds. They find that the nonselective MCR agonist melanotan II (MTII) effectively reduces ethanol consumption in both Mc3r-deficient and wild-type mice, indicating that the MC3 receptor is not critical for this effect. However, intracerebroventricular infusion of the highly selective MC4R agonist decreases ethanol drinking, while administration of the MCR antagonist AgRP-(83-132) increases ethanol consumption. These results suggest that the MC4 receptor, rather than MC3 receptor, plays a role in MCR agonist-induced reduction of ethanol intake, and that antagonistic actions of AgRP-(83-132) lead to increased ethanol consumption. This indicates that compounds targeting MCRs could hold promise for treating alcohol abuse disorders in addition to obesity.

    You can read the full article at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1360238/

57. Catania A. The melanocortin system in leukocyte biology. Journal of leukocyte biology. 2007; 81(2):383-92.
    View Summary +

    The melanocortin system in leukocyte biology

    The review discusses the components of the melanocortin system, including melanocortin peptides, receptors (MCRs), and endogenous antagonists. Melanocortin peptides have various effects on the body, including anti-inflammatory and immunomodulatory effects. Leukocytes both produce and respond to melanocortins, making them a significant target for these peptides. Activation of MCRs by melanocortin ligands reduces inflammation by inhibiting the translocation of the NF-kappaB nuclear factor, which plays a pivotal role in the inflammatory process. The review explores how melanocortin peptides and receptors influence leukocyte biology, highlighting their role in regulating inflammation.

    You can read the full article at https://jlb.onlinelibrary.wiley.com/doi/full/10.1189/jlb.0706426

58. Getting SJ, Flower RJ, Perretti M. Agonism at melanocortin receptor type 3 on macrophages inhibits neutrophil influx. Inflammation research : official journal of the European Histamine Research Society … [et al.]. 1999; 48 Suppl 2:S140-1.
    View Summary +

59. Getting SJ, Gibbs L, Clark AJ, Flower RJ, Perretti M. POMC gene-derived peptides activate melanocortin type 3 receptor on murine macrophages, suppress cytokine release, and inhibit neutrophil migration in acute experimental inflammation. Journal of immunology (Baltimore, Md. : 1950). 1999; 162(12):7446-53
    View Summary +

    POMC gene-derived peptides activate melanocortin type 3 receptor on murine macrophages, suppress cytokine release, and inhibit neutrophil migration in acute experimental inflammation

    This study investigated the effects of ACTH-related peptides in a murine model of experimental gout. Systemic administration of ACTH4-10 and alpha- and beta-melanocyte stimulating hormones inhibited neutrophil accumulation without affecting blood cell counts or corticosterone levels. ACTH4-10 significantly reduced the release of the chemokine KC, a marker of inflammation. In vitro, ACTH and ACTH4-10 inhibited macrophage activation, including phagocytosis and KC release, with IC50 values of approximately 30 nM and 100 µM, respectively. The melanocortin receptor type 3/4 antagonist SHU9119 blocked the inhibitory effects of ACTH4-10 both in vitro and in vivo. Although melanocortin type 3 receptor mRNA was detected in mouse peritoneal macrophages, not type 4 receptor mRNA was found. The study suggests that the activation of melanocortin type 3 receptors by ACTH4-10 attenuates cytokine release from macrophages, providing an anti-inflammatory mechanism for ACTH that is independent of glucocorticoid release.

    You can read the abstract at https://pubmed.ncbi.nlm.nih.gov/10358199/

60. Getting SJ, Lam CW, Leoni G, Gavins FN, Grieco P, Perretti M. [D-Trp8]-gamma-melanocyte-stimulating hormone exhibits anti-inflammatory efficacy in mice bearing a nonfunctional MC1R (recessive yellow e/e mouse). Molecular pharmacology. 2006; 70(6):1850-5
    View Summary +

    [D-Trp8]-gamma-melanocyte-stimulating hormone exhibits anti-inflammatory efficacy in mice bearing a nonfunctional MC1R (recessive yellow e/e mouse)

    The study investigated the anti-inflammatory effects of melanocortin receptors (MC1 and MC3R) using a selective MC3R agonist called [d-Trp(8)]-gamma-melanocyte-stimulating hormone (MSH). Recessive yellow (e/e) mice with nonfunctional MC1R were used. [d-Trp(8)]-gamma-MSH activated MC3R in peritoneal macrophages, reducing cAMP accumulation and chemokine KC release triggered by urate crystals. Synthetic and natural MC3R antagonists, SHU9119 and AGRP, blocked the effect, while the MC4R antagonist HS024 did not. Systemic [d-Trp(8)]-gamma-MSH treatment inhibited KC release and cell accumulation induced by urate crystals. [d-Trp(8)]-gamma-MSH also induced the anti-inflammatory protein heme-oxygenase 1 (HO-1). The study suggests that [d-Trp(8)]-gamma-MSH could be developed for treating inflammatory conditions due to its dual mechanism involving cytokine/chemokine inhibition and HO-1 induction.

    You can read the abstract at https://pubmed.ncbi.nlm.nih.gov/16959942/

61. Leoni G, Patel HB, Sampaio AL. Inflamed phenotype of the mesenteric microcirculation of melanocortin type 3 receptor-null mice after ischemia-reperfusion. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2008; 22(12):4228-38.
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    Inflamed phenotype of the mesenteric microcirculation of melanocortin type 3 receptor-null mice after ischemia-reperfusion. FASEB journal : official publication of the Federation of American Societies for Experimental Biology

    This study investigated the role of melanocortin receptor type 3 (MC3R) in vascular inflammation. Using MC3R-null mice, the researchers found that these mice exhibited increased plasma extravasation, cell adhesion, and emigration after occlusion and reopening of the superior mesenteric artery. The MC3R-null mice also showed elevated expression of inflammatory molecules like CCL2, CXCL1, and myeloperoxidase. Both MC1R and MC3R were present in the inflamed mesenteric tissue, but only MC3R had a significant impact on vascular responses. Treating animals with a selective MC3R agonist led to reduced cell adhesion, emigration, and chemokine production, highlighting the inhibitory role of MC3R in regulating cell trafficking and local mediator generation in vascular inflammation.

    You can read the full article at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2700033/

62. Getting SJ, Riffo-Vasquez Y, Pitchford S. A role for MC3R in modulating lung inflammation. Pulmonary pharmacology & therapeutics. 2008; 21(6):866-73.
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    A role for MC3R in modulating lung inflammation

    In this study, researchers investigated the potential of melanocortin peptides as therapeutic agents for lung inflammation, both in allergic and non-allergic models. They identified that melanocortin receptor type 1 (MC1R) and type 3 (MC3R) are expressed on alveolar macrophages. Stimulation with the MC3R agonist [D-TRP(8)]-gamma-MSH and pan-agonist alpha-MSH increased cAMP levels in wild-type and recessive yellow (e/e) mice, but not in MC3R-null mice. In allergic and non-allergic inflammation models, alpha-MSH and [D-TRP(8)]-gamma-MSH reduced leukocyte accumulation and inhibited TNF-alpha release. These effects were significantly attenuated in MC3R-null mice, suggesting that MC3R activation plays a key role in mediating the anti-inflammatory effects of melanocortins. The study suggests that selective MC3R agonists could be promising anti-inflammatory agents for lung inflammation therapy.

    You can read the full article at https://www.sciencedirect.com/science/article/abs/pii/S1094553908000928?via%3Dihub