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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. This study used whole-cell patch-clamp recordings of ligand activated G-protein-activated inwardly rectifying potassium channel currents in mouse brain slices containing locus ceruleus (LC) neurons to determine the effects of prolonged stimulation of MOR on α(2)-adrenoceptor (α(2)-AR) function. The results show distinct and sequential development of homologous and heterologous desensitization during persistent stimulation of MOR in LC neurons with Met(5)-enkephalin (ME). ME stimulation of MOR promoted rapid homologous desensitization that reached a steady state after 5 min and partially recovered over 30 min. Longer stimulation of MOR (10 min) induced heterologous desensitization of α(2)-AR function that exhibited slower recovery than homologous desensitization. Heterologous (but not homologous) desensitization required β-arrestin-2 (βarr-2) because it was nearly abolished in βarr-2-knockout (ko) mice. Heterologous (but not homologous) desensitization was also prevented by inhibition of ERK1/2 and c-Src signaling in wild-type (wt) mouse LC neurons. Heterologous desensitization may be physiologically relevant during exposure to high doses of opioids because α(2)-AR-mediated slow inhibitory postsynaptic currents were depressed in wt but not βarr-2 ko LC neurons after prolonged exposure to opioids. Together, these findings demonstrate a novel mechanism by which βarr-2 can regulate postsynaptic responsiveness to neurotransmitter release.

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. The results show that morphine does cause short-term desensitization. The desensitization induced by morphine was slower and smaller then that induced by [MET](5)-enkephalin (ME). After a brief application of a saturating concentration of ME, the current induced by morphine was smaller, and desensitization was not observed. In tissue taken from morphine-treated animals, the peak current induced by morphine was the same as in untreated animals, but morphine-induced desensitization was facilitated. The results suggest that morphine, like other agonists, can initiate receptor desensitization to decrease signaling.