Cannabinoid-induced antinociception is mediated by a spinal alpha 2-noradrenergic mechanism

The present study examined whether descending noradrenergic and serotonergic systems mediate the antinociceptive effect of the prototypical cannabinoid, delta-9-tetrahydrocannabinol (delta 9-THC). Rats were administered vehicle or delta 9-THC (10 mg/kg, i.v.) and subsequently given an intrathecal (i.t.) injection of either the alpha 2-noradrenergic antagonist yohimbine, or the non-specific serotonin (5-HT) antagonist, methysergide, through chronically implanted spinal catheters. Whereas yohimbine significantly reversed the cannabinoid-induced elevation of tail-flick latencies, methysergide had no effect. To examine whether yohimbine was indeed blocking the antinociceptive effects of delta 9-THC through a spinal mechanism, it was administered i.t. at either the lumbar or the upper thoracic level of the spinal cord. Antinociception was significantly reduced when yohimbine was administered in the lumbar region; however, administration in the upper thoracic region failed to have an effect. In addition, the effect of i.t. administered yohimbine and methysergide was assessed on two other indices sensitive to cannabinoids, hypothermia and ring immobility. As previously reported, i.v. administration of delta 9-THC led to hypothermia as well as immobility in the ring test which were not blocked by i.t. administration of either monoamine antagonist. To the contrary, methysergide potentiated the hypothermic effect of delta 9-THC. These findings indicate that cannabinoids activate descending noradrenergic neurons resulting in antinociception via the stimulation of spinal alpha 2-adrenoceptors.