Sub-chronic exposure to morphine alters general anesthetic potency by differentially regulating the expression of neurotransmitter receptor subunits in mice

Abstract

BackgroundSub-chronic exposure to morphine can increase the potency of propofol but decrease the potency of ketamine by unknown mechanisms. The present study was designed to investigate the effects of sub-chronic exposure to morphine on the expression of neurotransmitter receptor subunits, which might contribute to the potency changes of ketamine and propofol in vivo. MethodsSub-chronic exposure to morphine was established by administering subcutaneous injections of morphine for 5 consecutive days. The median effective dose (ED50) of ketamine and/or propofol was measured on day 1, day 3, day 7 and day 15, after the last morphine dosage. Mice in the sham group received an equal volume of normal saline. The expressions of N-methyl D-aspartate (NMDA) receptor and γ-aminobutyric acid A (GABAA) receptor subunits in the forebrain were measured. Knockdown or overexpression of a subunit was used to determine the causality between the change in anesthetic potency and the expression of an identified receptor subunit. ResultsAfter sub-chronic exposure of mice to morphine, the expression of NMDA receptor 1 (NR1) was most elevated in the forebrain on day 1 (P < 0.0001 vs. sham). In contrast, the expression of GABAA receptor β3 (GABAARβ3) gradually decreased to its lowest level on day 7 (P = 0.005 vs. sham) in the forebrain. Regression analysis revealed that the expression of NR1 in the forebrain was relevant to the increased ED50 of ketamine (P = 0.0002), while the expression of GABAARβ3 in the forebrain was relevant to the decreased ED50 of propofol (P = 0.0051) after morphine exposure. Knockdown expression of NR1 in the forebrain reversed the elevated ED50 of ketamine after morphine treatment. Overexpression of GABAARβ3 in the forebrain increased the ED50 of propofol to the sham-level after morphine treatment. ConclusionsSub-chronic exposure to morphine can differentially modulate the expressions of NR1 and GABAARβ3 in mice, which may contribute to the changes in ED50 of ketamine and propofol in vivo.