Role of μ-Opioid Receptor in Modulation of Preproenkephalin mRNA Expression and Opioid and Dopamine Receptor Binding in Methamphetamine-Sensitized Mice

We examined mRNA expression of preproenkephalin (PPE), a precursor of the endogenous opioid peptide enkephalin, and ligand binding to opioid and dopamine receptors in the striatum and nucleus accumbens in methamphetamine (METH)-sensitized μ-opioid receptor (μ-OR) knockout mice and their wild-type controls. Animals received daily intraperitoneal (i.p.) injections of METH (0, 0.625, 2.5, or 10 mg/kg) for 7 consecutive days to induce sensitization. Brain tissues were taken for biochemical analysis on experimental day 11 (4 days after the last injection). Expression of PPE mRNA and ligand binding were determined by in situ hybridization and autoradiography, respectively. Results indicate that there is an increase in PPE mRNA expression and a decrease in μ-OR ligand binding in METH-sensitized wild-type mice. These changes were not detected in METH-sensitized μ-OR knockout mice. A significant increase in δ-opioid receptor (δ-OR) ligand binding was found in μ-OR knockout mice. After repeated METH exposure, striatal and nucleus accumbal dopamine D1 receptor binding was decreased in μ-OR knockout mice but was not changed in wild-type mice. D2 receptor ligand binding was increased in wild-type mice and exhibited a biphasic change, with a decrease at 0.625 and 2.5 mg/kg doses of METH and an increase with 10 mg/kg of METH, in μ-OR knockout mice. These findings suggest that the μ-OR is involved in the regulation of METH-induced changes in an endogenous opioid peptide and dopamine receptors.