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Journal of Neuroscience, Vol 11, 2574-2581, Copyright © 1991 by Society for Neuroscience
Transient homologous mu-opioid receptor desensitization in rat locus coeruleus neurons
GC Harris and JT Williams
Vollum Institute, Oregon Health Sciences University, Portland 97201.
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.
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