Transient homologous mu-opioid receptor desensitization in rat locus coeruleus neurons.

Opioid agonists hyperpolarize neurons of the locus coeruleus (LC) in the slice preparation. When opioids were applied at concentrations that caused a maximum hyperpolarization, the membrane potential hyperpolarized to a peak (about 30 mV) in the first minute and then declined over a period of 5 min. In addition, following the washout, the amplitude of the hyperpolarization induced by a lower concentration of opioid was significantly reduced as compared to control. The original response to both the low and the high concentrations of opioid recovered after removal of opioids for about 20 min. The decline in response, termed "acute desensitization," was observed only with concentrations of opioids that caused a maximum hyperpolarization and was dependent on the concentration of opioid applied (EC50 for [Met5]-enkephalin (ME), between 3 and 5 microM). The response to ME (300 nM) was reduced to 6% of control following washout of a 5-min application of ME (30 microM), whereas the response to noradrenaline (300 nM) was reduced to 75% of control. The acute desensitization therefore was selective for the opioid receptor with marginal cross-desensitization to the alpha 2-adrenoceptor-mediated hyperpolarization. The desensitization still occurred following treatment with beta-chlornaltrexamine (beta-CNA), to decrease receptor reserve, as well as in cells taken from animals treated chronically with morphine. The mechanism for the acute desensitization was investigated using agents thought to alter kinase activity. This acute desensitization may represent an initial stage in the development of tolerance produced by chronic administration of opioids.