Comparison of five benzodiazepine-receptor agonists on buprenorphine-induced mu-opioid receptor regulation.
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 mu-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 mu-cell surface receptor density at the lowest dose of 0.2 mg/kg. Besides, LPZ for which the effect on mu-opioid-receptor 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 mu-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.
Poisnel
Géraldine
G
Université de Caen, Campus Jules Horowitz, Caen, France.
Dhilly
Martine
M
Le Boisselier
Reynald
R
Barre
Louisa
L
Debruyne
Danièle
D
D000701:Analgesics, Opioid / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D001569:Benzodiazepines / Q000494:pharmacology*; D001665:Binding Sites; D001923:Brain Chemistry / Q000187:drug effects; D002047:Buprenorphine / Q000494:pharmacology*; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000378:metabolism / Q000493:pharmacokinetics; D058785:GABA-A Receptor Agonists; D007700:Kinetics; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D017450:Receptors, Opioid, mu / Q000187:drug effects* / Q000378:metabolism*
D000701:Analgesics, Opioid; D058785:GABA-A Receptor Agonists; D017450:Receptors, Opioid, mu; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D001569:Benzodiazepines; D002047:Buprenorphine