Brain effects of melanocortins

The melanocortins (, and -melanocyte-stimulating hormones: MSHs; adrenocorticotrophic hormone:ACTH), a family of pro-opiomelanocortin (POMC)-derived peptides having in common thetetrapeptide sequence His-Phe-Arg-Trp, have progressively revealed an incredibly wide range of extrahormonaleffects, so to become one of the most promising source of innovative drugs for many, importantand widespread pathological conditions.The discovery of their effects on some brain functions, independently made by William Ferrari andDavid De Wied about half a century ago, led to the formulation of the term “neuropeptide” at a timewhen no demonstration of the actual production of peptide molecules by neurons, in the brain, was stillavailable, and there were no receptors characterized for these molecules.In the course of the subsequent decades it came out that melanocortins, besides inducing one of themostcomplex and bizarre behavioural syndromes(excessive grooming, crises of stretchings and yawnings,repeated episodes of spontaneous penile erection and ejaculation, increased sexual receptivity), play akey role in functions of fundamental physiological importance as well as impressive therapeutic effectsin different pathological conditions.If serendipity had been an important determinant in the discovery of the above-mentioned first-noticedextra-hormonal effects of melanocortins, many of the subsequent discoveries in the pharmacology ofthese peptides (feeding inhibition, shock reversal, role in opiate tolerance/withdrawal, etc.) have been theresult of a planned research, aimed at testing the “pro-nociceptive/anti-nociceptive homeostatic system”hypothesis.The discovery of melanocortin receptors, and the ensuing synthesis of selective ligands with agonistor antagonist activity, is generating completely innovative drugs for the treatment of a potentiallyvery long list of important and widespread pathological conditions: sexual impotence, frigidity, overweight/obesity, anorexia, cachexia, haemorrhagic shock, other forms of shock, myocardial infarction,ischemia/reperfusion-induced brain damage, neuropathic pain, rheumathoid arthritis, inflammatorybowel disease, nerve injury, toxic neuropathies, diabetic neuropathy, etc.This reviewrecalls the history of these researches and outlines the pharmacology of the extra-hormonaleffects of melanocortins which are produced by an action at the brain level (or mainly at the brain level).In our opinion the picture is still incomplete, in spite of being already so incredibly vast and complex.So, for example, several of their effects and preliminary animal data suggest that melanocortins might beof concrete effectiveness in one of the areas of most increasing concern, i.e., that of neurodegenerativediseases.