Clorazepate affects cell surface regulation of δ and κ opioid receptors, thereby altering buprenorphine-induced adaptation in the rat brain

Concomitant abuse of buprenorphine (BPN) and benzodiazepines (BZD) may relate to a pharmacodynamic interaction between the two. The objective of the present work was to investigate the acute and chronic effects of clorazepate (CRZ) alone or in combination with BPN on selective κ opiate tritiated ligand [3H]-U69 593 and δ opiate radioligand [3H]-deltorphine II binding in the rat brain. Bmax (maximal receptor density) and Kd (the dissociation constant) were directly determined at different brain regions of interest (ROI) selected for high densities of κ and/or δ receptors in rats treated with BPN and/or CRZ. The agents were administered either once or for 21 consecutive days. Differences in Bmax and Kd (for both specific ligands) were related to drug treatment and receptor location. Globally, single BPN administration induced no changes in κ or δ opiate receptor binding, whereas repeated BPN administration up-regulated κ receptor density and decreased δ affinity. At the κ receptor level, repeated administration of CRZ acted only on Kd, whereas the δ receptor was up-regulated. Repeated addition of CRZ to BPN had no effect on κ receptor Bmax versus chronic controls. By significantly decreasing Bmax, CRZ nullified the effect of chronic BPN on the κ receptor. The modifications were strongest in the nucleus accumbens, where both types of receptor occur. Treatments had region-selective effects in some brain areas, such as the amygdala, periaqueductal gray matter, hypothalamus and caudate putamen. Increased μ and δ receptor densities would be expected to provide reinforcement by enhancing reward, and impairment of κ receptor availability would be expected to decrease aversion. The effects described are likely to influence addictive behavior among people abusing BZD and BPN.