Pharmacological interaction of opiates with various classes of centrally acting dopaminergic drugs

The comparative analgesic and sedative (narcosis potentiating) efficacy of mu and kappa opioids was studied as a function of time in rats and mice. The mu agonists, morphine and fentanyl, produced antinociceptive actions against both heat and chemical noxious agents, but the half-lives of their ED50s were longer in the writhing than in the hot plate test. The kappa agonist drugs, bremazocine, ethylketocyclazocine and pentazocine, proved to be inactive against heat nociception, and produced a potent, long-lasting analgesia in the acetic acid writhing test, similar to mu agonists. The combination of two mu agonists resulted in a synergistic interaction and a remarkable prolongation of antinociceptive action. When the kappa-drug bremazocine was coadministered with morphine, there was a significant prolongation of the duration of analgesic action, without any influence on the potency. The interactions of mu and kappa opioids with agonists and antagonists at dopamine receptors were also studied in narcosis. The time course of the naloxone-morphine antagonism in analgesiometric assays revealed similarities, when apparent pA2 values were estimated at the peak of agonist and antagonist activity, but it was different in the writhing test when the pA2 was determined 84 minutes after morphine administration (EDt1/2, half-life belonging to the ED50) while naloxone was given at its peak effect.