Morphine-like discriminative stimulus effects of buprenorphine and demethoxybuprenorphine in rats: Quantitative antagonism by naloxone

The interactions between the opioid antagonist naloxone and the opioids morphine, buprenorphine and demethoxybuprenorphine (DMB), an acid-catalyzed rearrangement product of buprenorphine, were evaluated quantitatively in rats trained to discriminate between saline and 3.0 mg/kg of morphine using a two-choice, shock avoidance procedure. Dose-effect curves for each of the three agonists were determined alone and in the presence of varying doses of naloxone (0.01-1.0 mg/kg). Buprenorphine and DMB produced dose-related increases in morphine-appropriate responding which plateaued over at least a 30-fold dose-range for each drug. On a molar basis, buprenorphine was approximately 140 times and DMB approximately 45 times more potent than morphine. Naloxone produced parallel shifts in the dose-effect curves for morphine, buprenorphine and DMB. Schild plots derived from the relative shifts in the dose-effect curves yielded regression lines with slopes which were not significantly different from -1, consistent with naloxone acting as a competitive antagonist of each of the three opioids. The apparent pA₂ values for naloxone were 7.85 ± 0.36 against morphine, 7.48 ± 0.16 against buprenorphine and 7.17 ± 0.27 against DMB. Because the 95% CLs overlapped for morphine and buprenorphine, but not for morphine and DMB, these results are consistent with the interpretation that naloxone is acting at the same receptor in antagonizing morphine and buprenorphine but naloxone may be acting in a more complex manner in antagonizing DMB. The effectiveness of naloxone in antagonizing equieffective doses of morphine (3.0 mg/kg), buprenorphine (0.03 mg/kg) and DMB (0.1 mg/kg) were also evaluated when naloxone was administered either 0 or 30 min after the agonist. When administered 0 min after each agonist, the dose of naloxone required to completely antagonize morphine, buprenorphine and DMB was 0.1, 0.3 and 1.0 mg/kg, respectively. The high doses of naloxone required to antagonize buprenorphine and DMB are consistent with the latter two drugs being partial agonists. When naloxone was administered 30 min after each of the agonists, naloxone (1.0 mg/kg) antagonized morphine completely, but doses of naloxone as high as 100 mg/kg failed to antagonize buprenorphine and DMB completely. These latter findings are consistent with the interpretation that buprenorphine and DMB dissociate from receptors very slowly in vivo.