Buprenorphine and Opioid Antagonism, Tolerance, and Naltrexone-Precipitated Withdrawal

Abstract

The dual antagonist effects of the mixed-action -opioid partial agonist/-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-(Ϫ) -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 Ն24 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 Ն30-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 -antagonist, but not the -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.

Effects of buprenorphine on behavioral tests for antidepressant and anxiolytic drugs in mice

“…This result agrees with previously published studies conducted in rats (Di Chiara and Imperato 1988; Maisonneuve et al 1994). Co-treatment with BPN (0.25 mg/kg), the lowest dose that was active behaviorally in the FST and NIH tests, prevented U50,488 from reducing DA levels supporting other reports that BPN is a potent antagonist of KORs (Richards and Sadee 1985; Leander 1987; Paronis and Bergman 2011). Moreover, BPN alone was ineffective at altering DA levels.…”

“…Drug-induced hyperactivity make the results obtained in the FST ambiguous regarding antidepressant activity since increased activity can account for the reduction of immobility. Based on BPN’s slow receptor kinetics/receptor dissociation rates and on previous studies with selective KOR antagonists like nor-BNI where behavioral testing in the FST in rats was performed 24 h after administration, BPN was subsequently tested in the mouse FST 24 h post-administration (Cowan and Lewis 1995; Carr et al 2010; Paronis and Bergman 2011). Interestingly, a single injection of BPN produced protracted antidepressant-like and anxiolytic effects lasting at least 48 h (data not shown).…”

“…No evidence for behavioral tolerance to the antidepressant-like and anxiolytic responses was found; in fact the anxiolytic response was even larger following 6 d of BPN. In contrast, tolerance to some behavioral effects of BPN has been shown to develop following repeated administration (Glover and Davis 2008; Gringauz et al 2001; Paronis and Bergman 2011). Several studies have shown that chronic treatments with conventional antidepressants also retain their antidepressant-like effect in both the mouse and rat FST (Detke et al 1997; Cryan et al 2005; Jiao et al 2011).…”

Sustained opioid antagonism modulates striatal sensitivity to baby schema in opioid use disorder

“…Participants then received an injection of XRNTX (380 mg of naltrexone HCL gradually released from dissolvable polymer microspheres over a period of one month, manufactured by Alkermes plc, Dublin, Ireland, under the brand name Vivitrol ® ). As part of the consent procedure, participants were briefed about the loss of pharmacological effects of opioids resulting from the XRNTX treatment, and the dangers of attempting to overcome the opiate receptor blockade with higher than usual opioid doses (Paronis & Bergman, 2011; Ruan, Chen, Gudin, Couch, & Chiravuri, 2010). …”

The Role of Delta Opioid Receptors in Ethanol Consumption and Seeking: Implications for New Treatments for Alcohol Use Disorders

“…As naltrexone has been shown to block morphine-mediated analgesia in mice (Yan et al, 2003) and in rats (Nielsen et al, 2008), naltrexone treatment may therefore interfere with pain-relieving medications. Furthermore, as naltrexone can precipitate withdrawal symptoms in opioid-dependent rats (Adams & Holtzman, 1990) and monkeys (Paronis & Bergman, 2011), naltrexone treatment may potentially lead to exacerbation of withdrawal-induced hyperalgesia in alcohol-withdrawn patients. Although opioid receptor agonists with highest affinity for the MOP-R, such as morphine and methadone, have been widely used in the clinic for the treatment of pain (Nissen et al, 2001;Peng et al, 2008), preclinical studies have also demonstrated that KOP-R and DOP-R both play roles in analgesia.…”