Comparison of Five Benzodiazepine-Receptor Agonists on Buprenorphine-Induced μ-Opioid Receptor Regulation

Abstract

Abstract. In this study, we compared the effects of five short-, medium-, or long-acting benzodiazepine-receptor agonists (BZDs) [alprazolam (APZ), clonazepam (CLZ), flunitrazepam (FLZ), loprazolam (LPZ), zolpidem (ZLP)], at two distinct doses, 0.2 and 2 mg/kg, on the cell surface regulation of μ-opioid receptor induced by 0.15 mg/kg buprenorphine (BPN) in specific regions of the rat brain. Using 0.312 -5 nM [ 3 H]-DAMGO concentrations and Scatchard plot analysis, B max (maximal receptor density) and K d (dissociation constant) were determined at different brain regions of interest (amygdala, cortex, hippocampus, hypothalamus, thalamus). Acute BPN induced an expected down-regulation and addition of each of the BZDs to BPN induced less down-regulation than did BPN alone, sometimes while altering affinity. Some significant differences in the intensity of these effects were observed between BZDs. FLZ that is widely abused and enlarges BPN toxicity appeared the most potent to increase μ-cell surface receptor density at the lowest dose of 0.2 mg/kg. Besides, LPZ for which the effect on μ-opioidreceptor regulation appeared lower is considered to have a low risk of dependence in the epidemiological data banks. CLZ and ZLP (2 mg/ kg) induced the strongest modification on μ-opioid-receptor density, but a substantial decrease in affinity could minimize the functional consequences. The reported changes were maximal in the amygdala, hippocampus, and thalamus. Among people using BPN and BZDs, the effects described here are likely to influence addictive behaviors and induce toxic effects that could be quantitatively different due to the quality of the BZD.

Methadone‐Related Deaths – Epidemiological, Pathohistological, and Toxicological Traits in 10‐year Retrospective Study in Vojvodina, Serbia

“…Moreover, Poisnel et al. suggested that benzodiazepines, concurrently administered with methadone to opioid addicts, induce μ‐receptor up‐regulation and increase recruitment of receptors allowing μ‐ligands greater accessibility, and this co‐administration may result in lethal respiratory depression . However, in contrast to the findings of Mikoalenko and Poisnel in cases of co‐intoxication with benzodiazepines, we (and other authors, too) did not find higher concentrations of methadone, when compared to cases of methadone toxicity alone .…”

Can the Chronic Administration of the Combination of Buprenorphine and Naloxone Block Dopaminergic Activity Causing Anti-reward and Relapse Potential?

“…FLZ that is widely abused and augments buprenorphine toxicity appeared the most potent to increase mu-cell surface receptor density at the lowest dose of 0.2 mg/kg. Among people using buprenorphine and benzodiazepines, the effects described here are likely to influence addictive behaviors and induce toxic effects that could be quantitatively different due to the quality of the benzodiazepines (Poisnel et al, 2009). …”

Teaching From Catastrophe: Using Therapeutic Misadventures From Hydromorphone to Teach Key Principles in Clinical Pharmacology

“…36 Sedative hypnotic drugs act synergistically with opioids by acting on receptors and channels distinct from mu opioid receptors. [37][38][39] Patients with underlying medical conditions, including obstructive sleep apnea and chronic obstructive pulmonary disease, also predispose to carbon dioxide retention, thereby placing these patients in an unfortunate positive feedback loop when opioids are administered to them at inappropriate doses or intervals. 20,40,41 Patients 2, 4, and 5 emphasize these principles.…”

“…Similarly, in patient 5, the benzodiazepine receptor agonist, zolpidem, which has been documented to augment the respiratory depressant effect of opioids, 39 was administered midway between the dosing of 11 mg of intravenous hydromorphone given over an interval of 6 hours.…”