Prolonged stimulation of μ-opioid receptors produces β-arrestin-2-mediated heterologous desensitization of α(2)-adrenoceptor function in locus ceruleus neurons.

Prolonged agonist stimulation of the μ-opioid receptor (MOR) initiates receptor regulatory events that rapidly attenuate receptor-mediated signaling (homologous desensitization). Emerging evidence suggests that persistent MOR stimulation can also reduce responsiveness of effectors to other G-protein-coupled receptors, termed heterologous desensitization. However, the mechanisms by which heterologous desensitization is triggered by MOR stimulation are unclear.

Mechanisms of rapid opioid receptor desensitization, resensitization and tolerance in brain neurons.

Agonists acting on µ-opioid receptors (MOR) are very effective analgesics but cause tolerance during long-term or repeated exposure. Intensive efforts have been made to find novel opioid agonists that are efficacious analgesics but can elude the signalling events that cause tolerance. µ-Opioid agonists differentially couple to downstream signalling mechanisms.

Cellular morphine tolerance produced by βarrestin-2-dependent impairment of μ-opioid receptor resensitization.

Chronic morphine treatment produces behavioral and cellular opioid tolerance that has been proposed to be caused by attenuated μ-opioid receptor (MOR) recovery from desensitization (resensitization). The process of MOR resensitization is thought to require βarrestin-2 (βarr-2)-dependent trafficking of desensitized receptors to endosomal compartments, followed by recycling of resensitized receptors back to the plasma membrane. However, there is little direct evidence for this, particularly in native neurons.

Association of mu-opioid receptor variants and response to citalopram treatment in major depressive disorder.

Objective: Because previous preclinical and clinical studies have implicated the endogenous opioid system in major depression and in the neurochemical action of antidepressants, the authors examined how DNA variation in the mu-opioid receptor gene may influence population variation in response to citalopram treatment.

Method: A total of 1,953 individuals from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study were treated with citalopram and genotyped for 53 single nucleotide polymorphisms (SNPs) in a 100-kb region of the OPRM1 gene. The sample consisted of Non-Hispanic Caucasians, Hispanic Caucasians, and African Americans.

Two distinct mechanisms mediate acute mu-opioid receptor desensitization in native neurons.

Sustained stimulation of G-protein coupled receptors (GPCRs) leads to rapid loss of receptor function (acute desensitization). For many GPCRs including the mu-opioid receptor (MOR), an accepted mechanism for acute desensitization is through G-protein coupled receptor kinase (GRKs) mediated phosphorylation of the receptor, which facilitates the binding of beta-arrestins (betaarrs) to the receptor and then promotes endocytosis. However, the mechanism(s) that mediate acute desensitization have not yet been well defined in native neurons.

Morphine-Induced mu-opioid receptor desensitization.

Morphine has been widely accepted as the opioid agonist that sustains signaling because it does not cause receptor desensitization or internalization. This notion has led to the hypothesis that long-term morphine treatment initiates downstream adaptations that underlie tolerance and dependence. This study uses whole-cell recordings from neurons in the locus ceruleus to measure the potassium current induced by morphine.

Chronic morphine treatment reduces recovery from opioid desensitization.

Tolerance and dependence result from long-term exposure to opioids, and there is growing evidence linking acute receptor desensitization to these more long-term processes. Receptor desensitization encompasses a series of events leading to the loss of receptor function and internalization. This study examines the onset and recovery from desensitization in locus ceruleus neurons recorded in brain slices taken from animals that have been chronically treated with morphine.