SPINAL MORPHINE CLONIDINE ANTINOCICEPTIVE SYNERGISM - INVOLVEMENT OF G-PROTEINS AND N-TYPE VOLTAGE-DEPENDENT CALCIUM CHANNELS/

When morphine and clonidine are coadministered into the spinal cord (i ntrathecally) the resulting antinociception is greater than would be e xpected if the drug responses were additive; thus, a synergistic inter action. The mechanism for this synergistic interaction was investigate d using agents which alter calcium channel function and G protein func tion. Drugs were administered intrathecally to mice and antinociceptio n was measured using the tail flick test. The L-type calcium channel a ntagonists nifedipine (15 mu g) and verapamil (15 mu g) and the N-type antagonist omega-conotoxin GVIA (3 and 30 ng) decreased ED50 values f or both morphine and clonidine-three- to five-fold. The L-type calcium channel activator Bay K 8644 had a biphasic effect; 1.7 ng increased, although 170 ng decreased, morphine and clonidine ED(50) values. None of the calcium channel modifiers affected the morphine/clonidine syne rgism. In mice pretreated with pertussis toxin (PTX, one, 10-ng dose 2 1 days previously), the morphine ED(50) value increased two-fold, alth ough the clonidine ED50 value was not changed. PTX pretreatment did no t alter the morphine/clonidine synergism. Also, in PTX-pretreated mice , nifedipine and 1.7 ng Bay K 8644 did not alter the morphine/clonidin e synergism. However, in PTX pretreated animals omega-conotoxin GVIA ( 3 ng) changed the morphine/clonidine synergism to an additive interact ion. Thus, both N-type calcium channels and PTX-sensitive G proteins a re likely involved in spinal morphine/clonidine synergism.