IMMUNOHISTOCHEMICAL EVIDENCE OF DOWN-REGULATION OF MU-OPIOID RECEPTORAFTER CHRONIC PL-017 IN RATS

In a previous study, mu-opioid receptor binding was decreased by chron ic treatment of rats with a mu-opioid receptor-selective agonist [CH(3 )Phe(3), n-Pro(4)]morphiceptin (PL-017) [Tao, P.L., Lee, H.Y., Chang, L.R.. Loh, H.H., 1990, Decrease in mu-opioid receptor binding capacity in rat brain after chronic PL-017 treatment. Brain Res. 526, 270-275] . However, there was a lack of correlation between the time course of receptor down-regulation and the loss of pharmacological effects of th e drug. In the current study, we used immunohistochemistry to reinvest igate this issue. Male Sprague-Dawley rats were chronically treated wi th PL-017 i.c.v. for 1, 3 or 5 days, using an escalating dosage paradi gm (0.75-6.0 mu g), which resulted in a 1.4 to 32-fold increase in the AD(50). Rat brains were removed, frozen, coronally sectioned (14 mu m ) and processed for mu, delta- or kappa-opioid receptor immunohistoche mistry by the avidin-biotin complex (ABO method. Significant decreases in OP3 immunodensity were found in many brain regions which are enric hed with OP3 after chronic treatment of PL-017. Time-dependent decreas es in OP3 were detected and reached a plateau around 3 days of PL-017 treatment. No significant change in OP1 or OP2 immunodensity after chr onic treatment with PL-017 was found. Our conclusion is that chronic t reatment with PL-017 of rats selectively down-regulates mu-opioid rece ptors in the brain. This may be an important mechanism for PL-017 tole rance. (C) 1998 Elsevier Science B.V.