Agonist—antagonist properties of phenoxybenzamine in antinociception and opiate dependence tests

Abstract

The doe—response curve for phenoxybenzamine inhibition of stereospecific 3H-naloxone binding in brain homogenates was found to shift to the right in the presence of 100 mM NaCl. From the ratios of the IC 50 in the presence of Na + to the IC 50 in the presence of Na + calculated in this study for phenoxybenzine and some opiates it was predicted that phenoxybenzamine would have mixed agonist—antagonist properties in antinociceoption and that its antagonist activity would be in the rank order: butorphanol (1.8) ⪢ phenoxybenzamine (4.3) > M2230 (5.7) > pentazocine (6.9) ⪢ levorphanol (13.6). Phenoxybenzamine antagonized the oxymorphone-induced Straub tail reaction in mice and induced the abstinence syndrome in non-withdrawn morpine-dependent mice as predicted by the Na + response ratio. In the mouse tail flick assay phenoxybenzamine acted like the mized agonist—antagonist benzomorphinas as predicted. In “physical dependence capabilty” phenoxybenzamine was intermediate between butorphanol and pentazocine as predicted by the Na + response ratios. The success of the Na + response ratio derived from phenoxybenzamine's properties in the vitro opiate binding assay in predicting the behavior and rank order of phenoxybenzamine in in vivo tests, plus the ability of naloxone to antagonize phenoxybenzamine's antinociceptive action suggest that phenoxybenzamine's antinociceptive action may be mediated by the brain opiate receptor rather than by central α-adrenergic receptor blockade.