Elsevier

Life Sciences

Volume 73, Issue 7, 4 July 2003, Pages 823-847
Life Sciences

Minireview
The role of melanocortins and their receptors in inflammatory processes, nerve regeneration and nociception

https://doi.org/10.1016/S0024-3205(03)00349-7Get rights and content

Abstract

The melanocortins are a family of bioactive peptides derived from proopiomelanocortin. Those peptides, included among hormones and comprising ACTH, α-MSH, β-MSH and γ-MSH, are best known mainly for their physiological effects, such as the control of skin pigmentation by α-MSH, and ACTH effects on pigmentation and steroidogenesis. Melanocortins are released in various sites in the central nervous system and in peripheral tissues, and participate in the regulation of multiple physiological functions. They are involved in grooming behavior, food intake and thermoregulation processes, and can also modulate the response of the immune system in inflammatory states. Research of the past decade provided evidence that melanocortins could elicit their diverse biological effects by binding to a distinct family of G protein-coupled receptors with seven transmembrane domains. To date, five melanocortin receptor genes have been cloned and characterized. Those receptors differ in their tissue distribution and in their ability to recognize various melanocortins. These advances have opened up new horizons for exploring the significance of melanocortins, their ligands and their receptors for a variety of important physiological functions. We reviewed the origin of MSH peptides, the function and distribution of melanocortin receptors and their endogenous and exogenous ligands and the role of melanocortins and their receptors in inflammatory processes, nerve regeneration and nociception. Moreover, we analyzed their interaction with opioid peptides and finally, we discussed the postulated role of the melanocortin system in pain transmission at the spinal cord level.

Introduction

The melanocortin peptides, which include adrenocorticotropic hormone (ACTH), α-melanocyte stimulating hormone (α-MSH), β-MSH and γ-MSH are derived from a 31- to 36-kDa precursor protein, proopiomelanocortin (POMC) [1]. The main site of their synthesis is the pituitary gland. α-MSH was isolated in 1955 from the pituitary extracts as one of the first peptide hormones. In the fifties, the amino acid sequence of ACTH and β-MSH were also reported. Analysis of the amino acid sequence of the isolated peptides has revealed that MSH is a part of ACTH and that α-MSH, β-MSH and ACTH share the same core sequence Met-Glu-His-Phe-Arg-Trp-Gly, moreover, β-MSH appeared to be a part of β-lipotropin (β-LPH). In the late seventies, the sequence of their precursor, proopiomelanocortin was established [2]. When the POMC gene was cloned, mRNA expression studies showed the existence of the brain melanocortin system, separate from the pituitary. In the rat brain, POMC expression is confined largely to the arcuate nucleus of the hypothalamus (Arc) and nucleus tractus solitarius (NTS) of the medulla. From these discrete sources, melanocortinergic fibers project widely throughout the brain. In general, the major site of POMC synthesis in the brain is the arcuate nucleus of the hypothalamus. Compared to the arcuate POMC neurons, the NTS cells contain much lower levels of POMC mRNA. The presence of POMC-derived peptides in central nervous system (CNS) pathways as well as in the pituitary gland, an integral component of the hypothalamo-pituituary-adrenal (HPA) axis, involved in stress-related phenomena, suggests that POMC may serve as a link between endogenous pain control and stress response systems in the body [3]. POMC contains also in its structure the amino acid sequences homological to the structures of a variety of peptides with different biological functions, which are generated via tissue-specific cleavage.

There is a growing body of evidence from many recent studies indicating that melanocortins and melanocortin receptors are crucially implicated in a variety of important functions, beside their effect on melanocytes. Melanocortins possess a large number of multifarious actions, inducing stimulatory action on learning, attention and memory, motor effects and inhibition of food intake. Finally, there is a strong evidence that among POMC-derived peptides, melanocortins are the ones that exert a variety of immunomodulatory and anti-inflammatory activities, and facilitate regeneration of injured nerves [4], [5], [6]. The latter functions have recently attracted much interest since melanocortins are the target of the search for better antinociceptive drugs in chronic pain, especially inflammatory and neuropathic pain. Moreover, they share a common precursor molecule, POMC, with opioid peptides, e.g. β-endorphin, and seem to counteract the opioid effects, like nociception, tolerance etc, which is of interest in coping with side effects of opioids. Therefore, in this paper we review the functions of melanocortins, particularly those which are connected with they role in inflammation, injury and pain.

Section snippets

Melanocortin system

POMC sequence comprises the sequence of the melanocortin peptides: ACTH, α-, β-, γ-MSH. POMC also contains one copy of the opioid-defining amino acid sequence, Tyr-Gly-Gly-Phe-Met; which is found at the NH2-terminus of the opioid peptide, β-endorphin (β-End), and lipotropic hormone (LPH). Peptide hormones and transmitters are synthesized as high molecular weight precursors, prohormones, which are processed to yield smaller active fragments. The proteolytic processing of POMC occurs through

Immune system modulation

POMC peptides are produced by many different cells and tissues including the immune system and skin. All major constituents of the epidermis such as keratinocytes, Langerhans cells and melanocytes were found to express POMC mRNA and to release POMC-derived peptides [55]. Growing number of publications indicate that MSH peptides have a board capacity to inhibit inflammatory processes, viz. α-MSH was shown inhibit the inflammation in experimental bowel disease [56], [57], arthritis, brain

Conclusions

We have reviewed some aspects of a very large and expanding range of research on melanocortin peptides. At present, one of the problems inspiring the widest interest is the role of melanocortins in the regulation of immune system. The activation of melanocortin receptors on glial and peripheral immune cells modulates inflammatory responses and it should promote the control of inflammatory diseases. α-MSH analogues may aid the treatment of a variety of CNS and peripheral inflammatory disorders

Acknowledgements

This research was supported by statutory funds from the State Committee for Scientific Research (KBN; Warsaw).

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