Biomedical subjects

R A Adan

Publications and source records attributed to R A Adan.

At least 19 recordsLinked to original sources

PubMed2001

Neuropathic pain: a possible role for the melanocortin system?

In humans, damage to the nervous system can lead to a pain state referred to as neuropathic pain. Here, we give a short overview of the clinical picture and classification of neuropathic pain and highlight some of the currently known pathophysiological mechanisms involved, with special emphasis on neuropeptide plasticity. In this context, we discuss a specific group of neuropeptides, the melanocortins. These peptides have been demonstrated to play a role in nociception and to functionally interact with the opiate system. Recently, we demonstrated that spinal melanocortin receptors are upregulated in a rat model of neuropathic pain and that blockade of the melanocortin MC(4) receptor has anti-allodynic effects in this condition, suggesting that the melanocortin system plays a role in neuropathic pain. A natural agonist of melanocortin receptors is alpha-melanocyte-stimulating hormone (alpha-MSH), derived from the precursor molecule pro-opiomelanocortin (POMC). Cleavage of this precursor also yields beta-endorphin, which is co-released with alpha-MSH in nociception-associated areas of the spinal cord. We hypothesise that melanocortin receptor blockade attenuates a tonic influence of alpha-MSH on nociception, thus allowing the analgesic effects of beta-endorphin to develop, resulting in the alleviation of allodynia. In this way, treatment with melanocortin receptor antagonists might enhance opioid efficacy in neuropathic pain, which would be of great benefit in clinical practice.

Animals↗

PubMed2001

Hypothalamic, metabolic, and behavioral responses to pharmacological inhibition of CNS melanocortin signaling in rats.

The CNS melanocortin (MC) system is implicated as a mediator of the central effects of leptin, and reduced activity of the CNS MC system promotes obesity in both rodents and humans. Because activation of CNS MC receptors has direct effects on autonomic outflow and metabolism, we hypothesized that food intake-independent mechanisms contribute to development of obesity induced by pharmacological blockade of MC receptors in the brain and that changes in hypothalamic neuropeptidergic systems known to regulate weight gain [i.e., corticotropin-releasing hormone (CRH), cocaine-amphetamine-related transcript (CART), proopiomelanocortin (POMC), and neuropeptide Y (NPY)] would trigger this effect. Relative to vehicle-treated controls, third intracerebroventricular (i3vt) administration of the MC receptor antagonist SHU9119 to rats for 11 d doubled food and water intake (toward the end of treatment) and increased body weight ( approximately 14%) and fat content ( approximately 90%), hepatic glycogen content ( approximately 40%), and plasma levels of cholesterol ( approximately 48%), insulin ( approximately 259%), glucagon ( approximately 80%), and leptin ( approximately 490%), whereas spontaneous locomotor activity and body temperature were reduced. Pair-feeding of i3vt SHU9119-treated animals to i3vt vehicle-treated controls normalized plasma levels of insulin, glucagon, and hepatic glycogen content, but only partially reversed the elevations of plasma cholesterol ( approximately 31%) and leptin ( approximately 104%) and body fat content ( approximately 27%). Reductions in body temperature and locomotor activity induced by i3vt SHU9119 were not reversed by pair feeding, but rather were more pronounced. None of the effects found can be explained by peripheral action of the compound. The obesity effects occurred despite a lack in neuropeptide expression responses in the neuroanatomical range selected across the arcuate (i.e., CART, POMC, and NPY) and paraventricular (i.e., CRH) hypothalamus. The results indicate that reduced activity of the CNS MC pathway promotes fat deposition via both food intake-dependent and -independent mechanisms.

Animals↗

PubMed2001

Common requirements for melanocortin-4 receptor selectivity of structurally unrelated melanocortin agonist and endogenous antagonist, Agouti protein.

The activity of melanocortin receptors (MCR) is regulated by melanocortin peptide agonists and by the endogenous antagonists, Agouti protein and AgRP (Agouti-related protein). To understand how the selectivity for these structurally unrelated agonists and antagonist is achieved, chimeric and mutants MC3R and MC4R were expressed in cell lines and pharmacologically analyzed. A region containing the third extracellular loop, EC3, of MC4R was essential for selective Agouti protein antagonism. In addition, this part of MC4R, when introduced in MC3R, conferred Agouti protein antagonism. Further mutational analysis of this region of MC4R demonstrated that Tyr(268) was required for the selective interaction with Agouti protein, because a profound loss of the ability of Agouti protein to inhibit (125)I-labeled [Nle(4),d-Phe(7)]alpha-melanocyte-stimulating hormone (MSH) binding was observed by the single mutation of Tyr(268) to Ile. This same residue conferred selectivity for the MC4R selective agonist, [d-Tyr(4)]MT-II, whereas it inhibited interaction with the MC3R-selective agonist, [Nle(4)]Lys-gamma(2)-MSH. Conversely, mutation of Ile(265) in MC3 (the corresponding residue of Tyr(268)) to Tyr displayed a gain of affinity for [d-Tyr(4)]MT-II, but not for Agouti protein, and a loss of affinity for [Nle(4)]Lys-gamma(2)-MSH as compared with wild-type MC3R. This single amino acid mutation thus confers the selectivity of MC3R toward a pharmacological profile like that observed for MC4R agonists but not for the antagonist, Agouti protein. Thus, selectivity for structurally unrelated ligands with opposite activities is achieved in a similar manner for MC4R but not for MC3R.

Agouti Signaling Protein↗

PubMed2001

Drug target discovery by pharmacogenetics: mutations in the melanocortin system and eating disorders.

The identification of the genetic defect underlying the obese phenotype of the viable yellow mouse, ectopic overexpression of the agouti protein which acts as antagonist at the melanocortin-4 receptor, together with the demonstration that the brain melanocortin system was one major downstream effector pathway of leptin signaling has put forward melanocortin receptors as drug targets for obesity. The lack of compounds acting as melanocortin receptor antagonists was the reason why pharmacological studies had not recognized melanocortin receptors as important drug targets earlier. Blockade of brain melanocortin receptors results in increased food intake and body weight, whereas stimulation of the brain melanocortin system results in decreased food intake and activation of the hypothalamo-pituitary-adrenal axis. Anorexia nervosa is characterized by decreased body weight and food intake accompanied by changes in neuroendocrine systems such as strong activation of the hypothalamo-pituitary-adrenal axis. Since agouti-related protein suppresses the activity of the melanocortin system, the AgRP gene was investigated as candidate gene in anorexia nervosa. One variant of the AgRP gene was associated with anorexia nervosa, thus putting forward melanocortin receptor blockade as putative pharmacotherapy. Investigating variations in candidate genes in disease populations appears to be a fruitful approach towards the identification of drug targets.

Animals↗

PubMed2001

Association between an agouti-related protein gene polymorphism and anorexia nervosa.

Anorexia nervosa (AN) is a life threatening disorder affecting mostly adolescent women. It is a dramatic psychiatric syndrome accompanied by severe weight loss, hyperactivity and neuroendocrine changes (reviewed in Refs 1 and 2). Several studies have shown a strong genetic component in AN (reviewed in Ref 3). Recent advances in unraveling the mechanisms of weight control point to a crucial role of the melanocortin-4 receptor (MC4-r) system in regulating body weight. The orexigenic neuropeptide agouti-related protein (AGRP), a MC4-r antagonist, plays a crucial role in maintaining body weight, by inducing food intake. The sequence of the coding region of the human AGRP gene (AGRP) was determined and the AGRP of 100 patients with AN was screened for variations. Three single nucleotide polymorphisms (SNPs) were identified and screened in a further 45 patients and 244 controls. Two alleles were in complete linkage disequilibrium and were significantly enriched in anorectic patients (11%; P = 0.015) compared to controls (4.5%). These data indicate that variations of AGRP are associated with susceptibility for AN. This is possibly caused by defective suppression of the MC4-r by the variant AGRP, leading to a decreased feeding signal, increasing the risk of developing AN. These results implicate that antagonism of the MC4-r might be considered as pharmacotherapy for patients with AN.

Adolescent↗

PubMed2001

Chronic blockade of melanocortin receptors alleviates allodynia in rats with neuropathic pain.

UNLABELLED: We investigated the involvement of the spinal cord melanocortin (MC) system in neuropathic pain. Because we recently demonstrated that MC receptor ligands acutely alter nociception in an animal model of neuropathic pain, in this study we tested whether chronic administration was also effective. We hypothesized that chronic blockade of the spinal MC system might decrease sensory abnormalities associated with this condition. The effects of the MC receptor antagonist SHU9119 (0.5 microg/d) and agonist MTII (0.1 microg/d) were evaluated in rats with a chronic constriction injury of the sciatic nerve. Drugs were continuously infused into the cisterna magna. Antinociceptive effects were measured with tests involving temperature (10 degrees C or 47.5 degrees C) or mechanical (von Frey) stimulation. The administration of MTII increased mechanical allodynia, whereas SHU9119 produced a profound cold and mechanical antiallodynia, altering responses to control levels. The antiallodynic effects of SHU9119 were very similar to those produced by the alpha(2)-adrenergic agonist tizanidine (50 microg/d). The effects of SHU9119 and MTII are most likely mediated through the MC4 receptor, because this is the only MC-receptor subtype present in the spinal cord. We conclude that the chronic administration of MC4-receptor antagonists might provide a promising tool in the treatment of neuropathic pain. IMPLICATIONS: In this study we demonstrated that continuous intrathecal infusion of the melanocortin-receptor antagonist SHU9119 reduces cold and mechanical allodynia in rats with a chronic constriction injury of the sciatic nerve, a lesion producing neuropathic pain.

Adrenergic alpha-Agonists↗

PubMed2001

AgRP(83-132) acts as an inverse agonist on the human-melanocortin-4 receptor.

The central melanocortin (MC) system has been demonstrated to act downstream of leptin in the regulation of body weight. The system comprises alpha-MSH, which acts as agonist, and agouti-related protein (AgRP), which acts as antagonist at the MC3 and MC4 receptors (MC3R and MC4R). This property suggests that MCR activity is tightly regulated and that opposing signals are integrated at the receptor level. We here propose another level of regulation within the melanocortin system by showing that the human (h) MC4R displays constitutive activity in vitro as assayed by adenylyl cyclase (AC) activity. Furthermore, human AgRP(83-132) acts as an inverse agonist for the hMC4R since it was able to suppress constitutive activity of the hMC4R both in intact B16/G4F melanoma cells and membrane preparations. The effect of AgRP(83-132) on the hMC4R was blocked by the MC4R ligand SHU9119. Also the hMC3R and the mouse(m)MC5R were shown to be constitutively active. AgRP(83-132) acted as an inverse agonist on the hMC3R but not on the mMC5R. Thus, AgRP is able to regulate MCR activity independently of alpha-MSH. These findings form a basis to further investigate the relevance of constitutive activity of the MC4R and of inverse agonism of AgRP for the regulation of body weight.

Adenylyl Cyclases↗

PubMed2000

Antagonism of the melanocortin system reduces cold and mechanical allodynia in mononeuropathic rats.

The presence of both pro-opiomelanocortin-derived peptides and melanocortin (MC) receptors in nociception-associated areas in the spinal cord suggests that, at the spinal level, the MC system might be involved in nociceptive transmission. In the present study, we demonstrate that a chronic constriction injury (CCI) to the rat sciatic nerve, a lesion that produces neuropathic pain, results in changes in the spinal cord MC system, as shown by an increased binding of (125)I-NDP-MSH to the dorsal horn. Furthermore, we investigated whether intrathecal administration (in the cisterna magna) of selective MC receptor ligands can affect the mechanical and cold allodynia associated with the CCI. Mechanical and cold allodynia were assessed by measuring withdrawal responses of the affected limb to von Frey filaments and withdrawal latencies upon immersion in a 4.5 degrees C water bath, respectively. We show that treatment with the MC receptor antagonist SHU9119 has a profound anti-allodynic effect, suggesting that the endogenous MC system has a tonic effect on nociception. In contrast, administration of the MC4 receptor agonists MTII and d-Tyr-MTII primarily increases the sensitivity to mechanical and cold stimulation. No antinociceptive action was observed after administration of the selective MC3 receptor agonist Nle-gamma-MSH. Together, our data suggest that the spinal cord MC system is involved in neuropathic pain and that the effects of MC receptor ligands on the responses to painful stimuli are exerted through the MC4 receptor. In conclusion, antagonism of the spinal melanocortin system might provide a new approach in the treatment of neuropathic pain.

Animals↗

PubMed2000

Melanocortins and the brain: from effects via receptors to drug targets.

The lack of specific receptors (and antagonists) has hampered the research on the neural mechanism of action of adrenocorticotropic hormone (ACTH)- and melanocyte-stimulating hormone (MSH)-like peptides. Yet the original observations in the 1970s already pointed to cAMP as a possible mediator of ACTH/MSH effects in neurons. The cloning of melanocortin receptors since 1992, the identification of at least two subtypes (melanocortin MC(3) and MC(4) receptors) that are present in neural tissue and the development of selective and potent agonists as well as antagonists have markedly furthered the position of melanocortins as important neuropeptides. In this paper we discuss the role of especially the receptor subtype melanocortin MC(4) in various behaviors including grooming behavior and feeding behavior and consider new insights in the interaction between the opioid and the melanocortin system at the level of the spinal cord (i.e. pain perception). Finally, based on new data obtained in molecular pharmacological studies on brain melanocortin receptors, we suggest a general concept for selective receptor-ligand interaction: ligand residues outside the peptide core-sequence may direct the conformation of the residues in the ligand core-sequence that interact directly with the receptor-binding pocket and thereby determine selectivity.

Adrenocorticotropic Hormone↗

PubMed2000

Melanin-concentrating hormone, melanocortin receptors and regulation of luteinizing hormone release.

Melanin-concentrating hormone (MCH) is a neuropeptide, identified by its ability to either mimic or antagonize the melanin-dispersing action of alpha-melanocyte stimulating hormone (alphaMSH) on skin melanophores. MCH and alphaMSH also have antagonistic actions in the brain affecting feeding behaviour, aggression, anxiety, arousal and reproductive function through the release of luteinizing hormone (LH). It is not clear, however, how they exert their opposite effects in the central nervous system (CNS). One possibility is that they act via a common receptor. In this study we have examined the effect of a number of MC receptor antagonists, with relative selectivity for the MC3, 4 and 5 subtypes, on the actions of MCH on LH release. We confirmed that bilateral administration of MCH (100 and 200 ng/side) into the medial preoptic area of oestrogen-primed (oestradiol benzoate 5 microgram) ovariectomized anaesthetized rats, stimulated the release of LH. This effect was blocked by the concomitant administration into the medial preoptic area of the MC4/5 antagonist ([D-Arg8]ACTH(4-10) and the MC3/5 antagonist ([Ala6]ACTH(4-10)-both at 500 ng/side-but not by the MC3/4 antagonist, SHU9119 (200 ng/side). Furthermore, the MC3 agonist [Nle3]-gamma2 MSH failed to affect LH release. These results indicate that the MC3 and MC4 receptors are not involved in mediating the action of MCH but are consistent with an action via the MC5 subtype. Preputial glands, which express MC5 receptors, were also stimulated by MCH which is in keeping with this idea. In HEK293 cells transfected with the MC5 receptor MCH increased the production of IP3. However, it was much less potent than alphaMSH and unlike alphaMSH, had no effect on the production of cAMP. MCH (10-10 to 10-5 M) also failed to displace I125NDP-MSH from cells transfected with MC5 receptors indicating that it was not acting as a competitive antagonist and its binding site was distinct from that of alphaMSH. Thus while MCH may function as an agonist at the MC5 receptor, its stimulation of LH release is more likely to be mediated via a specific MCH receptor that has common properties with the MC5 receptor.

Adrenocorticotropic Hormone↗

PubMed2000

The effect of leptin on luteinizing hormone release is exerted in the zona incerta and mediated by melanin-concentrating hormone.

The adipose hormone, leptin, not only restrains appetite, but also influences energy expenditure. One such influence is to promote sexual maturation and fertility. The neuromodulatory circuits that mediate this effect are not well known but the present study suggests that one mediator could be melanin-concentrating hormone (MCH). We show that the long-form receptor (Ob-Rb) is expressed in the zona incerta of the rat and that administration of leptin (both 0.5 microg and 1.0 microg/side) into this area of ovariectomized, oestrogen-primed rats stimulated the release of luteinizing hormone (LH) within 1 h, the effect enduring for a further 1 h. Injections of leptin into the arcuate nucleus induced a smaller, transient rise in LH while injections into the paraventricular and ventromedial nuclei were without effect. MCH neurones are present in the zona incerta and administration of this hormone into the medial preoptic area (mPOA) stimulates LH release, therefore we investigated the possibility that MCH might mediate this effect of leptin. An injection of MCH antiserum into mPOA prevented the rise in LH normally induced by leptin injected into the zona incerta. In addition, melanocortin receptor antagonists ([D-Arg8]ACTH(4-10) and [Ala6]ACTH(4-10)), previously shown to inhibit the stimulatory effect of MCH on LH release, also inhibited the effect of leptin. We propose that one route by which leptin may promote reproductive activity is by enhancing MCH release from fibres within the mPOA. Speculative mechanisms for the action of MCH include the following possibilities: MCH may be acting on the specific MCH receptor which in turn interacts with a melanocortin or melanocortin-like receptor; MCH may bind directly to one of the melanocortin receptors; or melanocortin antagonists may interact with the MCH receptor.

Alternative Splicing↗

PubMed1999

Melanocortins and the treatment of nervous system disease. Potential relevance to the skin?

For several decades melanocortins have been implicated in the modulation of brain function. More recently, this idea has been supported by the identification and cloning of melanocortin (MC) receptors in the nervous system. MCs stimulate axonal growth in fetal neural tissue or in neural cell lines in culture. This feature was utilized in screening their neurotrophic or neuroprotection potential in animal studies of nervous system disease (peripheral nerve and spinal cord trauma, toxic and metabolic neuropathies, EAN, EAE, etc.). Some of these effects may be mediated by MC4 receptor activation, although as yet unknown receptors may also be involved (for instance, protection by Org 2766). To what extent MC-nervous system effects are related to known effects of MCs in skin- and neuro-immune systems, remains to be discovered. Nevertheless, it is of interest to note that activation of brain MC4 receptors profoundly affects care behavior for the body surface (skin and fur). The excessive grooming response in rodents exhibits a remarkable functional correlation with MSH activity in a brain-skin axis.

Adrenocorticotropic Hormone↗

PubMed1999

Characterization of melanocortin receptor ligands on cloned brain melanocortin receptors and on grooming behavior in the rat.

Since the melanocortin MC3 and melanocortin MC4 receptors are the main melanocortin receptor subtypes expressed in rat brain, we characterized the activity and affinity of nine melanocortin receptor ligands using these receptors in vitro, as well as their activity in a well-defined melanocortin-induced behavior in the rat: grooming behavior. We report here that [D-Tyr4]melanotan-II and RMI-2001 (Ac-cyclo-[Cys4, Gly5, D-Phe7, Cys10]alpha-MSH-NH2) have significantly higher affinity and potency on the rat melanocortin MC4 receptor as compared to the rat melanocortin MC3 receptor. Nle-gamma-MSH (melanocyte-stimulating hormone) was the only ligand with higher affinity and potency on the rat melanocortin MC3 receptor. The potency order of melanocortin MC4 receptor agonists, but not that of melanocortin MC3 receptor agonists, fitted with the potency of these ligands to stimulate grooming behavior, when administered intracerebroventricularly. SHU9119 (Ac-cyclo-[Nle4, Asp5, D-Nal(2)7, Lys10]alpha-MSH-(4-10)-NH2) and RMI-2005 (Ac-cyclo-[Cys4, Gly5, D-Na](2)7, Nal(2)9, Cys10]alpha-MSH-(4-10)-NH2) were able to inhibit alpha-MSH-induced melanocortin receptor activity in vitro, as well as alpha-MSH-induced grooming behavior. Melanotan-II, [Nle4-D-Phe7]alpha-MSH and RMI-2001 were also effective in inducing grooming behavior when administered intravenously. In the absence of purely selective melanocortin MC(3/4) receptor ligands, we demonstrated that careful comparison of ligand potencies in vitro with ligand potencies in vivo, could identify which melanocortin receptor subtype mediated alpha-MSH-induced grooming behavior. Furthermore, blockade of novelty-induced grooming behavior by SHU9119 demonstrated that this physiological stress response is mediated via activation of the melanocortin system.

Amino Acid Sequence↗

PubMed1999

Conformation of the core sequence in melanocortin peptides directs selectivity for the melanocortin MC3 and MC4 receptors.

Melanocortin peptides regulate a variety of physiological processes. Five melanocortin receptors (MC-R) have been cloned and the MC3R and MC4R are the main brain MC receptors. The aim of this study was to identify structural requirements in both ligand and receptor that determine gamma-melanocyte-stimulating hormone (MSH) selectivity for the MC3R versus the MC4R. Substitution of Asp10 in [Nle4]Lys-gamma2-MSH for Gly10 from [Nle4]alpha-MSH, increased both activity and affinity for the MC4R while the MC3R remained unaffected. Analysis of chimeric MC3R/MC4Rs and mutant MC4Rs showed that Tyr268 of the MC4R mainly determined the low affinity for [Nle4]Lys-gamma2-MSH. The data demonstrate that Asp10 determines selectivity for the MC3R, however, not through direct side chain interactions, but probably by influencing how the melanocortin core sequence is presented to the receptor-binding pocket. This is supported by mutagenesis of Tyr268 to Ile in the MC4R which increased affinity and activity for [Nle4]Lys-gamma2-MSH, but decreased affinity for two peptides with constrained cyclic structure of the melanocortin core sequence, MT-II and [D-Tyr4]MT-II, that also displayed lower affinity for the MC3R. This study provides a general concept for peptide receptor selectivity, in which the major determinant for a selective receptor interaction is the conformational presentation of the core sequence in related peptides to the receptor-binding pocket.

Adenylyl Cyclases↗

PubMed1999

Expression of melanocortin receptors and pro-opiomelanocortin in the rat spinal cord in relation to neurotrophic effects of melanocortins.

Although neurotrophic effects of alpha-melanocyte-stimulating hormone (alpha-MSH) are well established, the mechanism underlying these effects is unknown. To identify candidate components of the signaling system that may mediate these effects, in the present study rat spinal cord, dorsal root ganglia, sciatic nerve and soleus muscle were analysed for the expression of the neural MC3, MC4 and MC5 receptors and for the expression of the melanocortin precursor pro-opiomelanocortin (POMC). In rat lumbar spinal cord, the MC4 receptor was the only MC receptor subtype for which mRNA was detectable using RNAse protection assays. In situ binding studies using 125I-NDP-MSH, a synthetic alpha-MSH analogue, demonstrated MC receptor protein in the rat spinal cord, predominantly localised in substantia gelatinosa and area X, surrounding the central canal. Furthermore, POMC mRNA was demonstrated in rat spinal cord and dorsal root ganglia. These findings suggest a functional melanocortin system in the rat spinal cord, that might be involved in peripheral nerve repair. Regulation of POMC or MC receptor transcripts does not appear to be involved in the response to peripheral nerve crush in rats, since no change in mRNA expression patterns was detected after sciatic nerve crush, using quantitative RNAse protection assays. Nevertheless, subtle changes in melanocortin receptor binding did occur postsurgically in several regions of the spinal cord in both sham-operated and sciatic nerve-lesioned rats. The robust expression of MC receptor protein in spinal cord regions that are generally associated with nociception suggests a potentially broader involvement of endogenous melanocortins in spinal pathways which mediate the responses to peripheral injury, in addition to any direct melanocortin effects on sprouting and neurite outgrowth.

Animals↗

PubMed1998

Melanocortins and cardiovascular regulation.

The melanocortins form a family of pro-opiomelanocortin-derived peptides that have the melanocyte-stimulating hormone (MSH) core sequence, His-Phe-Arg-Trp, in common. Melanocortins have been described as having a variety of cardiovascular effects. We review here what is known about the sites and mechanisms of action of the melanocortins with respect to their effects on cardiovascular function, with special attention to the effects of the gamma-melanocyte-stimulating hormones (gamma-MSHs). This is done in the context of present knowledge about agonist selectivity and localisation of the five melanocortin receptor subtypes cloned so far. gamma2-MSH, its des-Gly12 analog (= gamma1-MSH) and Lys-gamma2-MSH are 5-10 times more potent than adrenocorticotropic hormone-(4-10)(ACTH-(4-10)) to induce a pressor and tachycardiac effect following intravenous administration. The Arg-Phe sequence near the C-terminal seems to be important for full in vivo intrinsic activity. Related peptides with a C-terminal extension with (gamma3-MSH) or without the Arg-Phe sequence (alpha-MSH, as well as the potent alpha-MSH analog, [Nle4,D-Phe7]alpha-MSH), are, however, devoid of these effects. In contrast, ACTH-(1-24) has a depressor effect combined with a tachycardiac effect, effects which are not dependent on the presence of the adrenals. Although the melanocortin MC3 receptor is the only melanocortin receptor subtype for which gamma2-MSH is selective, in vivo and in vitro structure-activity data indicate that it is not via this receptor that this peptide and related peptides exert either their pressor and tachycardiac effects or their extra- and intracranial blood flow increasing effect. We review evidence that the pressor and tachycardiac effects of the gamma-MSHs are due to an increase of sympathetic outflow to the vasculature and the heart, secondary to activation of centrally located receptors. These receptors are most likely localised in the anteroventral third ventricle (AV3V) region, a brain region situated outside the blood-brain barrier, and to which circulating peptides have access. These receptors might be melanocortin receptors of a subtype yet to be identified. Alternatively, they might be related to other receptors for which peptides with a C-terminal Arg-Phe sequence have affinity, such as the neuropeptide FF receptor and the recently discovered FMRFamide receptor. Melanocortin MC4 receptors and still unidentified receptors are part of the circuitry in the medulla oblongata which is involved in the depressor and bradycardiac effect of the melanocortins, probably via interference with autonomic outflow. Regarding the effects of the gamma-MSHs on cortical cerebral blood flow, it is not yet clear whether they involve activation of the sympathetic nervous system or activation of melanocortin receptors located on the cerebral vasculature. The depressor effect observed following intravenous administration of ACTH-(1-24) is thought to be due to activation of melanocortin MC2 receptors whose location may be within the peripheral vasculature. Melanocortins have been observed to improve cardiovascular function and survival time in experimental hemorrhagic shock in various species. Though ACTH-(1-24) is the most potent melanocortin in this model, alpha-MSH and [Nle4,D-Phe7]alpha-MSH and ACTH-(4-10) are quite effective as well. As ACTH-(4-10) is a rather weak agonist of all melanocortin receptors, it is difficult to determine via which of the melanocortin receptors the melanocortins bring about this effect. Research into the nature of the receptors involved in the various cardiovascular effects of the melanocortins would greatly benefit from the availability of selective melanocortin receptor antagonists.

Animals↗

PubMed1998

Asp10 in Lys-gamma2-MSH determines selective activation of the melanocortin MC3 receptor.

The melanocortin MC3 and MC4 receptors are the main melanocortin receptors expressed in brain. Of the endogenous melanocortins, gamma2-melanocortin stimulating hormone (MSH) selectively activates the melanocortin MC3 receptor, whereas alpha- and beta-MSH activate all melanocortin receptors. The aim was to gain an insight into the contribution of amino acids in positions 5 and 10 of melanocortins to the selectivity of [Nle4]Lys-gamma2-MSH for the melanocortin MC3 receptor versus the melanocortin MC4 receptor. Introduction of Asp10 into [Nle4]alpha-MSH as in [Nle4,Gly5,Asp10]alpha-MSH selectively increased the EC50 value for the melanocortin MC4 receptor. Conversely, removal of Asp10, as in [Nle4,Gly10]Lys-gamma2-MSH, selectively decreased the EC50 value for the melanocortin MC4 receptor. Thus, Asp10 in Lys-gamma2-MSH determined selectivity for the melanocortin MC3 receptor versus the melanocortin MC4 receptor.

Amino Acid Sequence↗

PubMed1998

The role of central melanocortin receptors in the activation of the hypothalamus-pituitary-adrenal-axis and the induction of excessive grooming.

1. In accord with previous studies intracerebroventricular (i.c.v.) injections of ACTH1-24 (1 microg) induced a display of excessive grooming, and increased the plasma concentrations of ACTH and corticosterone. Pituitary-adrenal activation was blocked by pretreatment with dexamethasone, indicating that the effect of the (i.c.v.) injected peptide was not caused by a peripheral effect on the adrenal cortex. 2. Doses of 1 and 3 microg of a non-selective melanocortin-3/4-receptor antagonist (SHU 9119), or of 5 and 10 microg of a selective melanocortin-4-receptor antagonist ([D-Arg8]ACTH4-10), coadministered (i.c.v.) with 1 microg ACTH1-24, inhibited the ACTH1-24-induced activation of the hypothalamus-pituitary-adrenal-axis and excessive grooming. 3. In addition, several doses of the selective melanocortin-3-receptor agonist Lys-gamma2-MSH were centrally administered, but neither neuroendocrine, nor excessive grooming responses were observed. 4. These results imply that the melanocortin-4-receptor, and not the melanocortin-3-receptor, is involved in the ACTH1-24-induced rise in plasma levels of ACTH and corticosterone, and excessive grooming.

Adrenocorticotropic Hormone↗