Immunohistochemical evidence of down-regulation of μ-opioid receptor after chronic PL-017 in rats

• Published in: European journal of pharmacology 1998-03, Vol.344 (2), p.137-142
• Main Authors: Tao, Pao-Luh, Han, Kuang-Fen, Wang, Shwun-De, Lue, Wei-Ming, Elde, Robert, Law, Ping-Yee, Loh, Horace H
• Format: Article
• Language: English
• Subjects: Animals; Antinociception; Biological and medical sciences; Brain - drug effects; Brain - metabolism; Down-Regulation; Drug Tolerance; Endorphins - pharmacology; Immunohistochemistry; Male; Medical sciences; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Opioid receptor; Pain Threshold - drug effects; Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems; Pharmacology. Drug treatments; PL-017; Rats; Rats, Sprague-Dawley; Receptors, Opioid - metabolism; Receptors, Opioid, mu - agonists; Receptors, Opioid, mu - metabolism; Tolerance
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/S0014-2999(97)01596-3

In a previous study, μ-opioid receptor binding was decreased by chronic treatment of rats with a μ-opioid receptor-selective agonist [CH 3Phe 3, d-Pro 4]morphiceptin (PL-017) [Tao, P.L., Lee, H.Y., Chang, L.R., Loh, H.H., 1990. Decrease in μ-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 μg), which resulted in a 1.4 to 32-fold increase in the AD 50. Rat brains were removed, frozen, coronally sectioned (14 μm) and processed for μ-, δ- or κ-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 μ-opioid receptors in the brain. This may be an important mechanism for PL-017 tolerance.