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


CONCLUSIONS
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.
Vrinten
D H
DH
Department of Medical Pharmacology and Anesthesiology, Rudolf Magnus Institute for Neurosciences, University Medical Centre Utrecht, Utrecht, the Netherlands.
Adan
R A
RA
Groen
G J
GJ
Gispen
W H
WH
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000818:Animals; D003080:Cold Temperature; D006358:Hot Temperature; D007278:Injections, Spinal; D008297:Male; D009074:Melanocyte-Stimulating Hormones / Q000494:pharmacology; D010146:Pain / Q000209:etiology / Q000503:physiopathology; D059408:Pain Management; D017288:Pain Threshold / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D011930:Reaction Time; D018043:Receptors, Corticotropin / Q000819:agonists / Q000037:antagonists & inhibitors / Q000187:drug effects* / Q000502:physiology; D044101:Receptors, Melanocortin; D012584:Sciatic Nerve / Q000293:injuries*; D013116:Spinal Cord / Q000378:metabolism; D000521:alpha-MSH / Q000031:analogs & derivatives* / Q000494:pharmacology
D000316:Adrenergic alpha-Agonists; D018043:Receptors, Corticotropin; D044101:Receptors, Melanocortin; C081720:alpha-MSH (4-10)amide, Ac-Nle(4)-cyclo(Asp(5)-Phe(7)-Lys(10))-; C103272:SHU 9119; D000521:alpha-MSH; D009074:Melanocyte-Stimulating Hormones