Evidence for a caudal brainstem site of action for cannabinoid induced hypothermia.

delta 9-Tetrahydrocannabinol (THC), 11-hydroxy delta 9-tetrahydrocannabinol (11-OH-THC) and the synthetic dimethylheptyl analogue of THC (DMHP) were injected intracerebrally into proven chemosensitive sites in the hypothalamus of unanesthetized cats with implanted microinjection guide tubes. 100 micrograms of each compound was administered in a volume of 8 microliters. Chemosensitivity of all injection sites was established by microinjection of carbamylcholine to induce hyperthermia and tetrodotoxin to induce hypothermia. THC or its analogues produced no significant change in body temperature when injected intracerebrally. However, in the same animals, parenteral administration of THC, 11-OH-THC or DMHP (0.5 to 2.0 mg/kg) induced hypothermic responses ranging from -2.0 to -7.0 degrees C. Intravenous administration of THC was effective in blocking shivering induced by cooling the preoptic region in unanesthetized cats with implanted thermodes. In cats with mid-pontine transections, cooling of the spinal cord by perfusion with an epidural double wall cannula at temperatures of 30, 20, 10 and 0 degrees C produced graded shivering which was recorded electromyographically. Intravenous THC, (0.25-2.0 mg/kg) produced a dose-dependent attenuation of spinal cord induced shivering. These data plus results of prior studies suggest that the tetrahydrocannabinols produce their hypothermic effect at sites in the caudal brainstem. Suppression of shivering at the ponto medullary or spinal cord level may represent an important mechanism which contributes to the lowering of body temperature.