MODULATION OF CANNABINOID-INDUCED ANTINOCICEPTION AFTER INTRACEREBROVENTRICULAR VERSUS INTRATHECAL ADMINISTRATION TO MICE - POSSIBLE MECHANISMS FOR INTERACTION WITH MORPHINE

Dose-effect curves were generated for the cannabinoids [intracerebrove ntricularly (icv.)] and compared with those previously generated after administration intrathecally (i.t.). The ED(50) values after administ ration of levonantradol, CP 55,940, Delta(9)-THC and Delta(8)-THC i.t. vs. icy. did not differ significantly. CP 56,667 was significantly mo re potent after icy. administration than i.t. administration, and was nearly 10 times more potent than CP 55,940 (icy.). CP 55,940 and CP 56 ,667, which did not produce greater than additive effects in combinati on with morphine when the drugs were administered i.t., shifted the mo rphine (icv.) dose-effect curve in a parallel manner nearly 10-fold af ter icy. administration. The antinociceptive effects of the cannabinoi ds (icy.) were not blocked by ICI 174,864 (20 mu g/mouse), nor-BNI (70 mu g/mouse) or naloxone (20 mu g/mouse or 10 mg/kg s.c.). Pertussis t oxin pretreatment i.t. for 7 days totally abolished the antinociceptio n produced by the cannabinoids (icy. and i.t.). Pretreatment of the mi ce with forskolin (i.t.) or Cl-cAMP (10 mu g/mouse i.t.), which produc ed no antinociception, significantly attenuated the antinociception pr oduced by the Delta(9)-THC and CP 55,940. However, when administered i cy., forskolin and Cl-cAMP produced antinociception, but did not block or produce greater than additive effects with the antinociception pro duced by the cannabinoids administered icy. The i.t. administration of calcium and calcium modulators failed to alter the antinociception pr oduced by the i.t. administration of the cannabinoids. Conversely, cal cium (icy.) blocked the antinociceptive effects of the cannabinoids. T he AD(50) values (+/-CL) for calcium-induced block of Delta(9)-THC, De lta(8)-THC and CP 55,940 were 215 (94-489), 176 (122-253) and 123 (81- 186) nmol/mouse, respectively. omega-Conotoxin (1 mu g/mouse icy.), wh ich did not alter the antinociceptive effects of Delta(9)-THC, signifi cantly reversed the calcium-induced blockade of Delta(9)-THC. Thapsiga rgin (icy.) blocked the antinociception produced by Delta(9)-THC and C P 55,940. Apamin, blocker calcium-gated potassium channels, produced a parallel rightward shift in the dose-effect curves of Delta(9)-THC, D elta(8)-THC and CP 55,940 (i.t.). However, apamin (5 ng/mouse icy.) fa iled to block icy, administered cannabinoids. Because acute administra tion of opiates/opioids have been shown to interact with G(i/o) protei n-coupled receptors, decrease calcium entry to and content of neurons, reduce cAMP levels and produce hyperpolarization of neurons via both ATP- and apamin-sensitive potassium channels, these three intracellula r systems may be common points of interaction with the cannabinoids.