Spirometric values for normal adult males in Greece.

Abstract

When morphine and clonidine are coadministered into the spinal cord (intrathecally) the resulting antinociception is greater than would be expected if the drug responses were additive; thus, a synergistic interaction. The mechanism for this synergistic interaction was investigated using agents which alter calcium channel function and G protein function. Drugs were administered intrathecally to mice and antinociception was measured using the tail flick test. The L-type calcium channel antagonists nifedipine (15 micrograms) and verapamil (15 micrograms) and the N-type antagonist omega-conotoxin GVIA (3 and 30 ng) decreased ED50 values for 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 ED50 values. None of the calcium channel modifiers affected the morphine/clonidine synergism. In mice pretreated with pertussis toxin (PTX, one, 10-ng dose 21 days previously), the morphine ED50 value increased two-fold, although the clonidine ED50 value was not changed. PTX pretreatment did not alter the morphine/clonidine synergism. Also, in PTX-pretreated mice, nifedipine and 1.7 ng Bay K 8644 did not alter the morphine/clonidine synergism. However, in PTX-pretreated animals omega-conotoxin GVIA (3 ng) changed the morphine/clonidine synergism to an additive interaction. Thus, both N-type calcium channels and PTX-sensitive G proteins are likely involved in spinal morphine/clonidine synergism.