Accelerated communciation: Constitutive μ opioid receptor activation as a regulatory mechanism underlying narcotic tolerance and dependence

Chronic administration of narcotic μ opioid agonists results in tolerance and dependence. We propose that agonist stimulation causes a gradual conversion of μ receptors to a constitutively active state μ∗ as a key step in tolerance and physical dependence. We provide evidence in support of the existence of μ∗ in human neuroblastoma cells, SH-SY5Y, and μ∗ upregulation during morphine treatment. Naloxone blocked μ∗ activity, acting as an antagonist with negative intrinsic activity which accounts for its high potency in eliciting withdrawal. In contrast, the μ selective antagonist CTAP did not affect μ∗ activity but inhibited naloxone's effect. The protein kinase inhibitor H7 was found to suppress μ∗ formation, suggesting that μ∗ is phosphorylated. In a model of acute morphine tolerance/dependence in mice, H7 prevented naloxone induced withdrawal jumping and reversed morphine (antinociceptive) tolerance. CTAP cause only mild withdrawal and attenuated naloxone induced withdrawal, as predicted for an antagonist without negative activity. These results support a role for constitutive μ receptor activation in narcotic tolerance and dependence, affording potential separation of acute and chronic narcotic effects.