The partial opioid agonist, buprenorphine, protects against lethal effects of cocaine

doi:10.1016/0376-8716(91)90037-Y

Drug and Alcohol Dependence

Volume 27, Issue 2, March 1991, Pages 177-184

https://doi.org/10.1016/0376-8716(91)90037-Y Get rights and content

Abstract

Buprenorphine (0.3–3.0 mg/kg) produced dose-dependent protection against the lethal effects of cocaine in mice. The (+)-enantiomer of buprenorphine did not protect up to doses over 100 times greater than the lowest effective dose of its (−)-enantiomer. The protective effects were also produced by the opioid agonists morphine and methadone, but not by the opioid antagonist, naltrexone. Low doses of naltrexone (0.3–1.0 mg/kg) blocked the protective effects of buprenorphine. Protection conferred by buprenorphine was not observed in CXBK mice, a recombinant inbred strain relatively devoid of mu-opioid receptors. Thus, buprenorphine appears to protect against the lethal effects of cocaine by a process mediated by mu-opioid receptors. The present results should provide some additional safety assurance in future clinical trials with buprenorphine, especially in outpatient trials where cocaine abuse may continue along with treatment.

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Pharmacological and genetic manipulation of kappa opioid receptors: Effects on cocaine- and pentylenetetrazol-induced convulsions and seizure kindling
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Citation Excerpt :
By contrast, buprenorphine, a μ opioid receptor (MOPr) agonist with low intrinsic activity and high receptor affinity (Cowan et al., 1977), attenuated the lethal effects of cocaine (Witkin et al., 1991). Although buprenorphine also acts as a KOPr-1 antagonist (Leander, 1987) its protective actions against cocaine toxicity were attributed to MOPr activation (cf. Witkin et al., 1991). The role of δ opioid receptors in cocaine-related toxicity is even less clear, since contrasting data concerning the same antagonist, naltrindole, have been reported (Braida et al., 1997; Patterson et al., 1997).
The present study used pharmacological and gene ablation techniques to examine the involvement of kappa opioid receptors (KOPr) in modulating the convulsant effects of two mechanistically different drugs: cocaine and pentylenetetrazol (PTZ; GABA-A receptor antagonist) in mice. Systemic administration of the selective KOPr-1 agonist, U69593 (0.16–0.6 mg/kg; s.c.), failed to modify cocaine-evoked convulsions or cocaine kindling. Similarly, no alteration in responsiveness to cocaine was observed in wild-type mice that received the selective KOPr-1 antagonist, nor-binaltorphimine (nor-BNI; 5 mg/kg) or in mice lacking the gene encoding KOPr-1. In contrast to cocaine, U69593 attenuated the seizures induced by acute or repeated PTZ administration. Nor-BNI decreased the threshold for PTZ-evoked seizures and increased seizure incidence during the initial induction of kindling relative to controls. Decreased thresholds for PTZ-induced seizures were also observed in KOPr-1 knock out mice. Together, these data demonstrate an involvement of endogenous KOPr systems in modulating vulnerability to the convulsant effects of PTZ but not cocaine. Furthermore, they demonstrate that KOPr-1 activation protects against acute and kindled seizures induced by this convulsant. Finally, the results of our study suggest that KOPr-1 antagonists will not have therapeutic utility against cocaine-induced seizures, while they may prove beneficial in attenuating several actions of cocaine that have been linked to its abuse.
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The abuse or therapeutic use of buprenorphine in combination with drugs that are more often abused than used therapeutically, such as cocaine, could also raise concerns regarding a potential for increased toxic effects secondary to the combined use of both drugs. Interestingly, a preclinical study revealed that buprenorphine (0.3 to 3.0 mg/kg intraperitoneally) protected against the lethal effects of cocaine-induced convulsions in mice.249 Cocaine (75 mg intraperitoneally) produced convulsions in all mice and lethal convulsions in 75% of the animals.
New effective analgesics are needed for the treatment of pain. Buprenorphine, a partial mu-opioid agonist which has been in clinical use for over 25 years, has been found to be amenable to new formulation technology based on its physiochemical and pharmacological profile. Buprenorphine is marketed as parenteral, sublingual, and transdermal formulations. Unlike full mu-opioid agonists, at higher doses, buprenorphine's physiological and subjective effects, including euphoria, reach a plateau. This ceiling may limit the abuse potential and may result in a wider safety margin. Buprenorphine has been used for the treatment of acute and chronic pain, as a supplement to anesthesia, and for behavioral and psychiatric disorders including treatment for opioid addiction. Prolonged use of buprenorphine can result in physical dependence. However, withdrawal symptoms appear to be mild to moderate in intensity compared with those of full mu agonists. Overdoses have primarily involved buprenorphine taken in combination with other central nervous system depressants.
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Cocaine produces a pattern of cardiovascular responses that are associated with apparent myocardial ischemia, arrhythmias, and other life-threatening complications in some individuals. Despite recent efforts to better understand the causes of cocaine-induced cardiovascular dysfunction, there remain a number of unanswered questions regarding the specific mechanisms by which cocaine elicits hemodynamic responses. This review will describe the actions of cocaine on the cardiovascular system and the evidence for the mechanisms by which cocaine elicits hemodynamic and pathologic responses in humans and animals. The emphasis will be on experimental data that provide the basis for our understanding of the mechanisms of cardiovascular toxicity associated with cocaine. More importantly, this review will identify several controversies regarding the causes of cocaine-induced cardiovascular toxicity that as yet are still debated. The evidence supporting these findings will be described. Finally, this review will outline the obvious deficits in our current concepts regarding the cardiovascular actions of cocaine in hope of encouraging additional studies on this grave problem in our society.
Antidotal effects of buprenorphine on the behavioral alterations accompanying cocaine and combined cocaine-ethanol toxicity
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The present study examined the effects of buprenorphine (BUP), a mixed opioid agonist–antagonist, on the behaviors accompanying cocaine (COCA) and combined cocaine–ethanol (EtOH) toxicity in the surviving mice. Using the activity-counting instrument Supermex, the relationship between the toxic signs and the corresponding behavioral alterations could be assessed. In the COCA-only group, a prolonged increase in the activity counts was caused by a high dose of COCA (75 mg/kg ip). Furthermore, this COCA-induced hyperactivity included ataxic behaviors that were accompanied by visible toxic signs, which were not observed in the mice with no drug treatment. A depressive dose of EtOH (3 g/kg ip) did not significantly modify the mortality rate in the COCA-only group in spite of its anticonvulsant effects. However, the peak activity counts in the survivors were attenuated in the COCA–EtOH group as compared to the COCA-only group. BUP attenuated the mortality rate in both COCA and COCA–EtOH groups, even without any anticonvulsant effects, but the most effective dose differed between the COCA (BUP: 0.25 mg/kg ip) and COCA–EtOH (BUP: 0.5 mg/kg ip) groups. At these BUP doses, the prolonged suppression of the morbid hyperactivity in the COCA–BUP group and the restoration of normal behavior in the COCA–EtOH–BUP group both seemed to be correlated with a good prognosis in the survivors; there was an early recovery from an increased blood pressure (BP), increased heart rate (HR) and decreased respiratory rate (RR) in the COCA–BUP group, and an early recovery from a decreased BP, decreased HR and decreased RR in the COCA–EtOH–BUP group.
Relationship between cocaine-induced hepatotoxic neurobehavioral and biochemical changes in mice: The antidotal effects of buprenorphine
2000, Life Sciences
Cocaine (COCA)-induced neurobehavioral symptoms, which can be observed simultaneously with exacerbation in biochemical markers, were evaluated in mice, and compared with the changes observed in a representative hepatic failure model induced by thioacetamide (TAA). The effects of pretreatment with buprenorphine (BUP) (0.25, 0.5 or 1 mg/kg i.p.), a mixed opioid agonist-antagonist and an antidote against fatal COCA toxicity, were also examined. At 5 min after the COCA administration (65 mg/kg i.p.), the liver ATP levels were attenuated, and an exacerbation of the CNS-stimulating effects of COCA could be characteristically observed for hepatotoxicity-related neurobehavioral symptoms (changes in alertness, interest, body tension, head movement and walking). At 24 h, the ALT (alanine aminotransferase) activity was elevated, and hepatotoxic attenuation was observed for all of the scores on the neurobehavioral symptoms; this was almost identical to the symptoms observed in the TAA-treated group of mice. Recovery was observed by 72 h for all of the morbid changes. The hepatotoxic biochemical changes and the sum score for all five neurobehavioral symptoms were significantly ameliorated by low doses (0.25 and 0.5 mg/kg) of BUP, both at 5 min and 24 h.
Protection against cocaine and combined cocaine-ethanol toxicities in mice by imidobenzodiazepine Ro 15-4513
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The effects of Ro 15-4513 in preventing cocaine and combined cocaine-ethanol toxicities were examined in mice. Ro 15-4513 is a partial inverse agonist of benzodiazepine receptors, which has been implicated in ethanol lethality and cocaine-induced seizures. Ro 15-4513 (5 mg/kg, 10 mg/kg, or 15 mg/kg) was administered intraperitoneally 10 min before the administration of saline and cocaine (75 mg/kg) in the cocaine groups, or before ethanol (3 g/kg) and cocaine (75 mg/kg) in the cocaine-ethanol groups. In both cocaine and cocaine-ethanol groups, two distinct groups of dead animals meeting the same criteria, the IL (immediate lethal) and DL (delayed lethal) groups, could be differentiated, depending on their survival times, observed disorders, and drug levels at the time of death. Differences in the seizure scores further subdivided the two groups. Ro 15-4513 protected mainly against the immediate lethality in the cocaine groups and mainly against the delayed lethality in the cocaine-ethanol groups. The dose of Ro 15-4513 providing the maximal protection against the lethal effects of these drugs was 10 mg/kg in the cocaine groups, and 5 mg/kg in the cocaine-ethanol groups. The sum of the lethalities was still higher with the maximal effective dose of Ro 15-4513 in the cocaine-ethanol groups than in the cocaine groups. In the cocaine-ethanol groups, 5 mg/kg of Ro 15-4513 attenuated both brain and liver cocaethylene levels. Cocaine-induced seizures were also attenuated by any dose of Ro 15-4513 used in the cocaine groups. Although some discrepancies were observed in the protective properties, some validity for the use of Ro 15-4513, a drug with more than one mode of protective action, was demonstrated in this study.

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The partial opioid agonist, buprenorphine, protects against lethal effects of cocaine

Abstract

Life Sci.

Life Sci.

Life Sci.

Biol. Psychiat.

Neuropharmacol.

Buprenorphine. Drug Alc. Depend.

Eur. J. Pharmacol.

Brain Res.

Life Sci.

Life Sci.

Life Sci.

A clinical trial of buprenorphine: Comparison with methadone in the detoxification of heroin addicts

Clin. Pharmacol. Ther.

Buprenorphine: Dose-related blockade of opioid challenge effects in opioid dependent humans

J. Pharmacol. Exp. Therap.

Naltrexone, morphine and cocaine interactions in mice and rats

J. Pharmacol. Exp. Therap.

Evaluation in nonhuman primates: Evaluation of the physical dependence capacities of oripavine-thebaine partial agonists in Patas monkeys

Agonist and antagonist properties of buprenorphine, a new antinociceptive agent

Br. J. Pharmacol.