Opioid desensitization: Interactions with G-protein-coupled receptors in the locus coeruleus

In rat locus coeruleus (LC) neurons, α₂ adrenoceptors, μ-opioid and somatostatin receptors all activate the same potassium conductance. Chronic treatment with morphine causes a loss of sensitivity that is specific to the μ-opioid response, with no change in the α₂ adrenoceptor-mediated response. Acute desensitization induced by opioid, somatostatin, and α₂- adrenoceptor agonists was studied in brain slices of rat LC using intracellular recording. A supramaximal concentration of the opioid agonist Met⁵-enkephalin induced a profound homologous desensitization but little heterologous desensitization to an α₂-adrenoceptor agonist (UK 14304) or somatostatin. All desensitized currents showed partial recovery. A supramaximal concentration of UK14304 caused a relatively small amount of desensitization. Although little interaction was observed among inhibitory G- protein-coupled receptors, activation of an excitatory receptor had marked effects on inhibitory responses. Muscarinic agonists, which produce an inward current in LC neurons, reduced the magnitude of agonist-induced outward currents and increased both the rate and amount of opioid desensitization. Muscarinic activation did not alter desensitization of α₂-adrenoceptor responses. Acute desensitization shares several characteristics with the tolerance induced by chronic morphine treatment of animals.