Methamphetamine-induced behavioral sensitization in mice: alterations in μ-opioid receptor

We had previously demonstrated that opioid receptors contribute to the induction and expression of behavioral sensitization induced by repeated daily injection with 2.5 mg/kg of methamphetamine for 7 days. Using the same regimen, the present study investigated the alterations in μ-opioid receptor during the induction (on days 2, 5, and 8) and expression (on days 11 and 21) periods of behavioral sensitization. Radioligand binding revealed that the maximal binding of μ-opioid receptor was not changed on days 2 and 5, but down-regulated on day 8. After cessation of drug treatment, the maximal binding of μ-opioid receptor gradually and time-dependently returned to normal level on day 11 and up-regulated on day 21. In contrast, no changes in δ- and κ-opioid receptors were detectable on any given day examined. The potency of DAMGO for [35S]-GTPγS coupling was enhanced on days 2, 5, 11, and 21. Moreover, 1 μM of naltrexone or β-chlornaltrexamine significantly suppressed the basal [35S]-GTPγS coupling on days 2, 11, and 21. These findings indicate enhanced responsiveness and elevated constitutive activity of μ-opioid receptor. In summary, our data clearly demonstrate that alterations in μ-opioid receptor are involved in and may contribute to the sensitization to locomotor stimulating effect of methamphetamine.