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KMID : 0379519990150030323
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한국독성학회지
1999 Volume.15 No. 3 p.323 ~ p.330
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Immunohistochemical Evidence of Down-Regulation of Rat Brain μ-Opioid Receptor after Chronic Etorphine Treatment
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Lee Jang-Hern
Elde Robert
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Abstract
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A compensatory decrease in the number of active receptor is one possible mechanism for the development of drug tolerance. This agonist induced down-regulation has been reported in several hormonal or neurotransmitter systems. However, there was a lack of correlation between the time course of receptor down-regulation and the loss of pharmacological effects of the drug. In this study, we utilized immunohistochemical technique to investigate the modulatory effect of chronic etorphine treatment to mu opioid receptor levels. Male Sprague-Dawley rat was rendered tolerant to etorphine by s.c. implantation of osmotic minipumps containing 3 mg/ml of etorphine HCl for 1 or 5 days. During this period, there was a time-dependent increase in the AD50 values of etorphine to inhibit the tail-flick response and an increase in naloxone-precipitated withdrawal signs. Rat brains were removed, frozen, coronally sectioned (14 ㎛) and processed for mu opioid receptor immunohistochemistry by the avidin-biotin complex (ABC) method. Significant decreases in mu opioid receptor immunodensity were observed in many brain regions such as cauputamen (CPu) , thalamic nucleus (TN), raphe nucleus (RN) and amygdalohippocampal area (Amy). Time dependent decreases in mu opioid receptor immunoreactivity were detected and reached a plateau around 5 days after chronic treatment of etorphine. No significant change in immunoreactivity of leuenkephalin after chronic treatment with etorphine was found. Our conclusion is that chronic treatment with etorphine of rats down regulates mu opioid receptors in the brain mediated by cellular internalization of receptor. This may be an important mechanism for etorphine tolerance.
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KEYWORD
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Etorphine, Antinociception, Tolerance, μ-opioid receptor, Down-regulation, Immunohis-tochemistry
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