EVALUATION OF CAMP INVOLVEMENT IN CANNABINOID-INDUCED ANTINOCICEPTION

It has been proposed that cannabinoids act at a Gi protein-coupled rec eptor to produce antinociception. One action of Gi-proteins is to decr ease intracellular cAMP via inhibition of adenylyl cyclase activity. A lthough cannabinoid inhibition of forskolin-stimulated adenylyl cyclas e is used as a confirmation of functional cannabinoid receptors, it is unknown whether this second messenger system specifically mediates ca nnabinoid-induced antinociception. This in vivo study was conducted us ing enantiomeric cAMP analogs, Rp-cAMPS (an antagonist) and Sp-cAMPS ( an agonist), and the cAMP agonist Cl-cAMP to test the hypothesis that cannabinoid-induced antinociception is due to decreased adenylyl cycla se activity. None of the cAMP analogs, forskolin, or 1,9-dideoxy-forsk olin affected Delta(9)-THC or CP-55,940-induced antinociception produc ed by intrathecal (i.t.) or intracerebroventricular (i.c.v.) injection s in mice. Experiments were also conducted to investigate whether i.c. v. administration of Sp-cAMPS would block i.c.v. cannabinoid-induced a ntinociception in rats. Sp-cAMPS failed to block CP-55,940-induced ant inociception. However, Sp-cAMPS produced hyper-excitability and reacti ve behavior indicating that it did elicit a pharmacological effect. Al though, adenylyl cyclase may mediate other cannabinoid-induced actions , these results do antinociception. Alternatively, other effector syst ems such as calcium or potassium channels coupled to cannabinoid recep tors may mediate cannabinoid-induced antinociception.