shu-9119 and Pain

The authors recently demonstrated that administration of the melanocortin-4 receptor antagonist SHU9119 decreased neuropathic pain symptoms in rats with a sciatic chronic constriction injury. The authors hypothesised that there is a balance between tonic pronociceptive effects of the spinal melanocortin system and tonic antinociceptive effects of the spinal opioid system. Therefore, they investigated a possible interaction between these two systems and tested whether opioid effectiveness could be increased through modulation of the spinal melanocortin system activity.. In chronic constriction injury rats, melanocortin and opioid receptor ligands were administered through a lumbar spinal catheter, and their effects on mechanical allodynia were assessed by von Frey probing.. Naloxone (10-100 microg) dose-dependently increased allodynia (percent of maximum possible effect of -67 +/- 9%), which is in agreement with a tonic antinociceptive effect of the opioid system. SHU9119 decreased allodynia (percent of maximum possible effect of 60 +/- 13%), and this effect could be blocked by a low dose of naloxone (0.1 microg), which by itself had no effect on withdrawal thresholds. Morphine (1-10 microg) dose-dependently decreased allodynia (percent of maximum possible effect of 73 +/- 14% with the highest dose tested). When 0.5 microg SHU9119 (percent of maximum possible effect of 47 +/- 14%) was given 15 min before morphine, there was an additive antiallodynic effect of both compounds.. Together, these data confirm that there is an interaction between the spinal melanocortin and opioid systems and that combined treatment with melanocortin-4 receptor antagonists and opioids might possibly contribute to the treatment of neuropathic pain.

Topics: alpha-MSH; Analgesics, Opioid; Animals; Drug Interactions; Endorphins; Male; Melanocyte-Stimulating Hormones; Morphine; Naloxone; Narcotic Antagonists; Pain; Physical Stimulation; Rats; Rats, Wistar; Receptor, Melanocortin, Type 4; Receptors, Corticotropin; Sensory Thresholds; Spinal Cord

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.. 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.

Topics: Adrenergic alpha-Agonists; alpha-MSH; Animals; Cold Temperature; Hot Temperature; Injections, Spinal; Male; Melanocyte-Stimulating Hormones; Pain; Pain Management; Pain Threshold; Rats; Rats, Wistar; Reaction Time; Receptors, Corticotropin; Receptors, Melanocortin; Sciatic Nerve; Spinal Cord