Chronic Morphine Exposure and μ‐opioid Receptor Phosphorylation Deficiency Enhances Opioid Sensitivity of Thalamo‐Striatal Synapses

Abstract

The pain relieving and rewarding properties of opioids are widely attributed to action at the μ-opioid receptor (MOR). Prolonged opioid administration results in analgesic tolerance, where increasing doses of drug are required to achieve the same effect. Tolerance develops to some opioid effects, such as analgesia and reward, more than others, such as respiratory depression and constipation. These effects are mediated through separate neural pathways, indicating MORs might be differentially regulated depending on where they are present. MOR signaling is regulated by receptor phosphorylation; upon activation by an agonist, MORs are subsequently phosphorylated at the carboxyl (C)-terminal tail and flagged for internalization, terminating signaling via associated G-proteins. Glutamatergic projections from the mediodorsal thalamus (MD) to the striatum are involved in processing the affective dimension of pain, or the negative emotion associated with perception of painful stimuli. MORs are present at these synapses, but how MOR signaling here is regulated is not well understood. The aim of this work was to determine how chronic opioid exposure alters opioid sensitivity at MORs present on thalamic terminals in the striatum, and whether opioid sensitivity is enhanced in MOR phosphorylation-deficient mice. We recorded optically evoked excitatory postsynaptic currents (EPSCs) in striatal medium spiny neurons in mouse brain slices. Opioid sensitivity was determined by measuring EPSC inhibition induced by MOR agonists morphine and met-enkephalin (ME). Chronic treatment with morphine enhanced EPSC inhibition by morphine, but not ME, at these receptors in wild-type (WT) mice. Drug-naïve MOR C-terminal phosphorylation-deficient mice showed enhanced EPSC inhibition by opioids compared to WT mice. The finding that chronic morphine exposure induced sensitization, rather than tolerance, to morphine at glutamatergic thalamo-striatal terminals suggests a synapse specific effect that contributes to tolerance overall. While MORs present at thalamo-striatal terminals showed increased, rather than decreased, opioid sensitivity, this effect may still be important in contributing to analgesic tolerance at the behavioral level. Future studies will investigate whether the enhanced opioid sensitivity following chronic opioid treatment is phosphorylation-dependent and how chronic morphine treatment alters signaling of downstream effectors of MOR.