Antagonism of morphine-like discriminative effects by beta-funaltrexamine

beta-Funaltrexamine (beta-FNA), an irreversible antagonist at the mu-opioid receptor, was administered intracisternally to rats discriminating between subcutaneous injections of saline and 3.0 mg/kg of morphine in order to reduce the size of the receptor reserve. beta-FNA alone (10 micrograms) occasioned substantial morphine-appropriate responding for at least 6 h but mainly saline-appropriate responding 24 h after administration, the pretreatment interval for most experiments. beta-FNA (3.0-30 micrograms) dose-dependently shifted to the right stimulus-generalization curves for morphine and fentanyl; 10 micrograms also shifted to the right the curves for meperidine and buprenorphine. In all cases, antagonism was fully surmounted by higher doses of the agonist, even after inactivation of more than 75% of mu-opioid receptors. This antagonist effect of beta-FNA is smaller than that reported previously in tests of analgesia, suggesting that the receptor reserve for the discriminative effects of morphine-like drugs is larger than the receptor reserve for their analgesic effects. beta-FNA produced larger rightward displacements of the morphine and buprenorphine curves than of the fentanyl curve and inactivated a larger fraction of the receptors acted upon by those drugs compared to fentanyl. Results with meperidine were intermediate. This suggests that the receptor population mediating morphine-like discriminative effects of fentanyl is not identical to the receptor population mediating these effects of morphine and buprenorphine.