Stereoselective action of (+)-morphine over (−)-morphine in attenuating the (−)-morphine-produced antinociception via the naloxone-sensitive sigma receptor in the mouse

We have previously demonstrated that (+)-morphine and (−)-morphine given spinally stereoselectively attenuate the spinally-administered (−)-morphine-produced tail-flick inhibition in the mouse. The phenomenon has been defined as antianalgesia. Present studies were then undertaken to determine if the systemic administration of (+)-morphine and (−)-morphine also stereoselectively attenuates the systemic (−)-morphine-produced tail-flick inhibition and the effects of (+)-morphine and (−)-morphine are mediated by the naloxone-sensitive sigma receptor activation in male CD-1 mice. Pretreatment with (+)-morphine at a dose of 0.01–10 ng/kg given subcutaneously dose-dependently attenuated the tail-flick inhibition produced by subcutaneously-administered (−)-morphine (5 mg/kg). Pretreatment with (−)-morphine (0.01–1.0 mg/kg) given subcutaneously also attenuates the (−)-morphine-produced tail-flick inhibition. The ED50 values for (+)-morphine and (−)-morphine for inhibiting the (−)-morphine-produced tail-flick inhibition were estimated to be 30.6 pg/kg and 97.5 μg/kg, respectively. The attenuation of the (−)-morphine-produced tail-flick inhibition induced by (+)-morphine or (−)-morphine pretreatment was reversed by the pretreatment with (+)-naloxone or by the sigma receptor antagonist BD1047 (N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(dimethylamino)ethylamine dihydrobromide) given subcutaneously. Pretreatment with (+)-pentazocine, a selective sigma receptor agonist, (1-10 mg/kg) given subcutaneously also attenuates (−)-morphine-produced tail-flick inhibition, which was restored by (+)-naloxone (4 mg/kg) or BD1047 (10 mg/kg) pretreated subcutaneously. It is concluded that (+)-morphine exhibits extremely high stereoselective action over (−)-morphine given systemically in attenuating the systemic (−)-morphine-produced antinociception and the antianalgesic effect of (+)-morphine and (−)-morphine is mediated by activation of the naloxone-sensitive sigma receptor.