GABAA receptor alpha6 subunit deficiency prevents development of morphine tolerance

Abstract

Previously, we compared periaqueductal gray (PAG) samples of morphine‐responsive vs ‐tolerant C57BL/6 mice in a gene array screen, and detected changes in GABAA receptor alpha6 subunit (Gabra6). I.c.v. injection of Gabra6 antisense, but not missense, prevented the increase in ED50 after chronic morphine. By real time RT‐PCR, chronic morphine caused a significant 5‐fold increase in PAG Gabra6 levels in missense‐injected animals, but no change in Gabra6 antisense‐injected mice. We have tested the role of Gabra6 further, in mice with a targeted deletion of the Gabra6 gene (Homanics et al., 1997). 129;B6 Gabra6−/− and their wild‐type littermates received either saline or escalating doses (10–40 mg/kg) of morphine s.c. bid for 3 d. On day 4, mice were tested in a cumulative morphine dose‐tail flick response assay. Chronic morphine induced a rightward shift in the dose‐response curve in WT, but not in Gabra6−/− mice. Thus, PAG Gabra6 expression was increased in morphine‐tolerant mice, whereas Gabra6 antisense blocked both increased expression and development of morphine tolerance. Moreover, Gabra6−/− mice did not develop morphine tolerance. GABAA receptors containing alpha6 have the highest affinity for GABA, are mostly extrasynaptic and may be involved in tonic inhibition. We hypothesize that Gabra6 expression is a compensatory mechanism for altered GABA tone upon chronic morphine treatment.Supported by PHS DA09444 and DA13471 (LY,) and University of Cincinnati Research Council (JTAM)