Buprenorphine and opioid antagonism, tolerance, and naltrexone-precipitated withdrawal

Abstract

The dual antagonist effects of the mixed-action μ-opioid partial agonist/κ-opioid antagonist buprenorphine have not been previously compared in behavioral studies, and it is unknown whether they are comparably modified by chronic exposure. To address this question, the dose-related effects of levorphanol, trans-(-)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl] benzeneacetamide (U50,488), heroin, and naltrexone on food-maintained behavior in rhesus monkeys were studied after acute and chronic treatment with buprenorphine (0.3 mg/kg/day). In acute studies, the effects of levorphanol and U50,488 were determined at differing times after buprenorphine (0.003-10.0 mg/kg i.m.). Results show that buprenorphine produced similar, dose-dependent rightward shifts of the levorphanol and U50,488 dose-response curves that persisted for ≥ 24 h after doses larger than 0.1 mg/kg buprenorphine. During chronic treatment with buprenorphine, the effects of levorphanol, U50,488, heroin, and naltrexone were similarly determined at differing times (10 min to 48 h) after intramuscular injection. Overall, results show that buprenorphine produced comparable 3- to 10-fold rightward shifts in the U50,488 dose-response curve under both acute and chronic conditions, but that chronic buprenorphine produced larger (10- to ≥ 30-fold) rightward shifts in the heroin dose-effect function than observed acutely. Naltrexone decreased operant responding in buprenorphine-treated monkeys, and the position of the naltrexone dose-effect curve shifted increasingly to the left as the time after daily buprenorphine treatment increased from 10 min to 48 h. These results suggest that the μ-antagonist, but not the κ-antagonist, effects of buprenorphine are augmented during chronic treatment. In addition, the leftward shift of the naltrexone dose-effect function suggests that daily administration of 0.3 mg/kg buprenorphine is adequate to produce opioid dependence.

Fig. 1.

Effects of buprenorphine (BUP) pretreatment on the response rate-decreasing effects of levorphanol. Single injections of BUP were given either 10 min (top) or 24 h (bottom) before determining the effects of levorphanol. Symbols and associated vertical lines represent the mean and S.E.M. obtained in three monkeys. Abscissae: cumulative dose of levorphanol in milligrams per kilograms of body weight. Ordinates: response rates expressed as a percentage of noninjection control response rates. Asterisks indicate that the levorphanol ED₅₀ value in the presence of BUP was significantly different from the control ED₅₀: *, p < 0.05; **, p < 0.01; ***, p < 0.001.

Fig. 2.

Effects of buprenorphine pretreatment on the response rate-decreasing effects of U50,488. Abscissae: cumulative dose of U50,488 in milligrams per kilograms of body weight. Asterisks indicate that the U50,488 ED₅₀ value in the presence of BUP was significantly different from the control ED₅₀: *, p < 0.05; **, p < 0.01; ***, p < 0.001.Other details are as in Fig. 1.

Fig. 3.

Effects of daily buprenorphine treatment on the response rate-decreasing effects of heroin. Heroin was injected using cumulative dosing procedures either before the onset of the daily dosing regimen (baseline) or at the indicated times after 0.32 mg/kg buprenorphine. Abscissae: cumulative dose of heroin in milligrams per kilograms of body weight. Asterisks indicate that the heroin ED₅₀ value in the presence of BUP was significantly different from the control ED₅₀: **, p < 0.01. Other details are as in Fig. 1.

Fig. 4.

Effects of daily buprenorphine treatment on the response rate-decreasing effects of U50,488. ***, p < 0.001. Other details are as in Figs. 2 and 3.

Fig. 5.

Effects of daily buprenorphine treatment on the response rate-decreasing effects of naltrexone. Top, increase potency of naltrexone as time after buprenorphine increases from 10 min to 48 h is shown. Bottom, recovery toward the baseline dose-effect function after termination of the daily dosing regimen is shown. Abscissae: cumulative dose of naltrexone in milligrams per kilograms of body weight; other details are as in Fig. 3. Asterisks indicate that the naltrexone ED₅₀ value in the presence of BUP was significantly different from the ED₅₀ value obtained at 10 min after BUP: *, p < 0.05; **, p < 0.01; ***, p < 0.001.