title: Immunohistochemical evidence of down-regulation of mu-opioid receptor after chronic PL-017 in rats.
abstract: In a previous study, mu-opioid receptor binding was decreased by chronic treatment of rats with a mu-opioid receptor-selective agonist [CH3Phe3, D-Pro4]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 the drug. In the current study, we used immunohistochemistry to reinvestigate this issue. Male Sprague-Dawley rats were chronically treated with PL-017 i.c.v. for 1, 3 or 5 days, using an escalating dosage paradigm (0.75-6.0 microg), which resulted in a 1.4 to 32-fold increase in the AD50. Rat brains were removed, frozen, coronally sectioned (14 microm) and processed for mu-, delta- or kappa-opioid receptor immunohistochemistry by the avidin-biotin complex (ABC) method. Significant decreases in OP3 immunodensity were found in many brain regions which are enriched with OP3 after chronic treatment of PL-017. Time-dependent decreases in OP3 were detected and reached a plateau around 3 days of PL-017 treatment. No significant change in OP1 or OP2 immunodensity after chronic treatment with PL-017 was found. Our conclusion is that chronic treatment with PL-017 of rats selectively down-regulates mu-opioid receptors in the brain. This may be an important mechanism for PL-017 tolerance.
authors.affiliation: Department of Pharmacology, National Defense Medical Center, Taipei, Taiwan, ROC.
authors.forename: P L
authors.initials: PL
authors.lastname: Tao
authors.forename: K F
authors.initials: KF
authors.lastname: Han
authors.forename: S D
authors.initials: SD
authors.lastname: Wang
authors.forename: W M
authors.initials: WM
authors.lastname: Lue
authors.forename: R
authors.initials: R
authors.lastname: Elde
authors.forename: P Y
authors.initials: PY
authors.lastname: Law
authors.forename: H H
authors.initials: HH
authors.lastname: Loh
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D015536:Down-Regulation; D004361:Drug Tolerance; D004723:Endorphins / Q000494:pharmacology*; D007150:Immunohistochemistry; D008297:Male; D017288:Pain Threshold / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011957:Receptors, Opioid / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000378:metabolism*
chemical_list: D004723:Endorphins; D011957:Receptors, Opioid; D017450:Receptors, Opioid, mu; C044708:morphiceptin, N-Me-Phe(3)-