Spinal and supraspinal components of cannabinoid-induced antinociception

The purpose of this study was to investigate whether cannabinoids produce antinociception spinal and supraspinal sites of action. The antinociceptive effect of delta 9-tetrahydrocannabinol (3 or 10 mg/kg), a naturally occurring cannabinoid, and CP-55,940 (0.1, 0.3, or 0.5 mg/kg), a potent synthetic cannabinoid, were assessed in spinally transected and intact rats. Each drug, administered i.v., produced a potent, long-lasting elevation of tail-flick latencies in the intact animals. This antinociception was significantly attenuated by spinal transection. Administration of each cannabinoid (i.t.) to the lumbar region of the spinal cord produced a weak, but long-enduring antinociceptive effect. In contrast, spinal administration of CP-55,940 to the upper thoracic region failed to elevate tail-flick latencies above base-line values. Additionally, i.t. administration of CP-55,940 (30 or 100 micrograms) continued to have a weak antinociceptive effect in spinal rats. In contrast, i.t. administration of CP-56,667, the (+)-enantiomer of CP-55,940, failed to elevate tail-flick latencies above base line at a dose of 1000 micrograms, thus indicating stereoselectivity. Finally, the biodisposition of 3H-delta 9-tetrahydrocannabinol after either i.v. or i.t. administration to spinal and intact rats was also assessed. The levels of radioactivity did not differ between spinal and intact animals in either whole brain, spinal cord, or plasma when the drug was administered i.v. When the drug was administered i.t., however, surgical transection of the spinal cord led to a decreased concentration of labeled substances in the whole brain and plasma. These converging lines of evidence indicate that cannabinoids produce antinociception through multiple mechanisms at the spinal and supraspinal levels of the central nervous system.