In rat locus coeruleus (LC) neurons, alpha(2) adrenoceptors, mu-opioid and somatostatin receptors all activate the same potassium conductance. Chronic treatment with morphine causes a loss of sensitivity that is specific to the mu-opioid response, with no change in the alpha(2) adrenoceptor-mediated response. Acute desensitization induced by opioid, somatostatin, and alpha(2)-adrenoceptor agonists was studied in brain slices of rat LC using intracellular recording, A supramaximal concentration of the opioid agonist Met(5)-enkephalin induced a profound homologous desensitization but little heterologous desensitization to an alpha(2)-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 alpha(2)-adrenoceptor responses. Acute desensitization shares several characteristics with the tolerance induced by chronic morphine treatment of animals.