M-current modulators alter rat spinal nociceptive transmission: an electrophysiological study in vitro

M-currents constitute a unique effector system to control neuronal excitability due to their voltage and ligand sensitivities. Here we have used retigabine, an M-current agonist, and XE-991, an M-current antagonist, to study the possible involvement of these currents in the processing of spinal sensory and motor processing of nociceptive information in normal, untreated rats. Experiments were performed in a hemisected spinal cord preparation from rat pups using extracellular recordings. Responses to activation of nociceptive and non-nociceptive afferent fibres were recorded. M-current modulators were bath applied to the entire cord or applied locally by pressure ejection. Retigabine and XE-991 produced long-lasting and concentration-dependent effects on nociceptive reflexes showing only minor effects on non-nociceptive reflexes. Retigabine depressed responses to repetitive stimulation of the dorsal root recorded from motor neurones and dorsal horn neurones, whereas XE-991 showed the opposite potentiatory effect and reversed effects of retigabine. Local application of the modulators close by motor nuclei produced changes in reflex responses similar to those caused by bath application. These results constitute a clear indication of the existence of functional M-currents in dorsal and ventral horn elements of the mammalian spinal cord where they may serve to regulate early sensory and motor processing of nociceptive information. The weak effect of modulators on non-nociceptive reflexes suggest that M-currents constitute a promising novel target for analgesics.