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.
Vrinten
D H
DH
Departments of Medical Pharmacology and Anesthesiology, Rudolf Magnus Institute for Neurosciences, University Medical Centre Utrecht, 3584 CG Utrecht, The Netherlands.
Gispen
W H
WH
Groen
G J
GJ
Adan
R A
RA
D000818:Animals; D001345:Autoradiography; D003080:Cold Temperature; D003250:Constriction; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006930:Hyperalgesia / Q000378:metabolism*; D007278:Injections, Spinal; D008024:Ligands; D008297:Male; D009074:Melanocyte-Stimulating Hormones / Q000008:administration & dosage; D009842:Oligopeptides / Q000494:pharmacology; D010147:Pain Measurement / Q000187:drug effects; D010812:Physical Stimulation; D051381:Rats; D017208:Rats, Wistar; D011930:Reaction Time / Q000187:drug effects; D044104:Receptor, Melanocortin, Type 3; D044105:Receptor, Melanocortin, Type 4; D018043:Receptors, Corticotropin / Q000008:administration & dosage / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000378:metabolism; D044101:Receptors, Melanocortin; D012584:Sciatic Nerve / Q000502:physiology / Q000601:surgery; D020426:Sciatic Neuropathy / Q000378:metabolism*; D012684:Sensory Thresholds / Q000187:drug effects; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism; D000521:alpha-MSH / Q000031:analogs & derivatives*
D008024:Ligands; D009842:Oligopeptides; D044104:Receptor, Melanocortin, Type 3; D044105:Receptor, Melanocortin, Type 4; D018043:Receptors, Corticotropin; D044101:Receptors, Melanocortin; C105974:acetyl-norleucyl(4)-(aspartyl(5)-histidyl(6)-phenylalanyl(7)-arginyl(8)-tryptophyl(9)-lysyl(10))cyclo-alpha-MSH(4-10)amide; C103272:SHU 9119; D000521:alpha-MSH; C027756:MSH, 4-Nle-7-Phe-alpha-; D009074:Melanocyte-Stimulating Hormones