Cannabinoid suppression of noxious heat-evoked activity in wide dynamic range neurons in the lumbar dorsal horn of the rat

The effects of cannabinoid agonists on noxious heat-evoked firing of 62 spi nal wide dynamic range (WDR) neurons were examined in urethan-anesthetized rats (1 cell/animal). Noxious thermal stimulation was applied with a Peltie r device to the receptive fields in the ipsilateral hindpaw of isolated WDR neurons. To assess the site of action, cannabinoids were administered syst emically in intact and spinally transected rats and intraventricularly. Bot h the aminoalkylindole cannabinoid WIN55,212-2 (125 mu g/kg iv) and the bic yclic cannabinoid CP55,940 (125 mu g/kg iv) suppressed noxious heat-evoked activity. Responses evoked by mild pressure in nonnociceptive neurons were not altered by CP55,940 (125 mu g/kg iv), consistent with previous observat ions with another cannabinoid agonist, WIN55,212-2. The cannabinoid induced -suppression of noxious heat-evoked activity was blocked by pretreatment wi th SR141716A(1 mg/kg iv), a competitive antagonist for central cannabinoid CB1 receptors. By contrast, intravenous administration of either vehicle or the receptor-inactive enantiomer WIN55,212-3 (125 mu g/kg) failed to alter noxious heat-evoked activity. The suppression of noxious heat evoked activ ity induced by WIN55,212-2 in the lumbar dorsal horn of intact animals was markedly attenuated in spinal rats. Moreover, intraventricular administrati on of WIN55,212-2 suppressed noxious heat-evoked activity in spinal WDR neu rons. By contrast, both vehicle and enantiomer were inactive. These finding s suggest that cannabinoids selectively modulate the activity of nociceptiv e neurons in the spinal dorsal horn by actions at CB1 receptors. This modul ation represents a suppression of pain neurotransmission because the inhibi tory effects are selective for pain-sensitive neurons and are observed with different modalities of noxious stimulation. The data also provide converg ing lines of evidence for a role for descending antinociceptive mechanisms in cannabinoid modulation of spinal nociceptive processing.