The effect of the irreversible μ-opioid receptor antagonist clocinnamox on morphine potency, receptor binding and receptor mRNA

• Published in: European journal of pharmacology Vol. 287; no. 2; pp. 135 - 143
• Main Authors: Chan, Kawa, Brodsky, Marina, Davis, Trong, Franklin, Steve, Inturrisi, Charles E., Yoburn, Byron C.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 12.12.1995; Elsevier
• Subjects: Analgesia; Animals; Binding, Competitive; Biological and medical sciences; Cinnamates - pharmacology; Clocinnamox; DAMGO ([ d-Ala 2,MePhe 4,Gly-ol 5]enkephalin); Dose-Response Relationship, Drug; DPDPE ([ d-Pen 2, d-Pen 5]enkephalin); Irreversible antagonist; Male; Medical sciences; Mice; Mice, Inbred Strains; Morphine; Morphine - pharmacology; Morphine Derivatives - pharmacology; mRNA; Narcotic Antagonists - pharmacology; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Opioid receptor alkylation; Opioid receptor antagonist; Opioid receptor binding; Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems; Pharmacology. Drug treatments; Receptors, Opioid, mu - drug effects; RNA, Messenger - metabolism; Solution hybridization; Time Factors; U69,593; Analgesia; Opioid receptor binding; U69,593; Clocinnamox; Irreversible antagonist; Morphine; Opioid receptor alkylation; mRNA; DPDPE ([ d-Pen 2, d-Pen 5]enkephalin); Opioid receptor antagonist; DAMGO ([ d-Ala 2,MePhe 4,Gly-ol 5]enkephalin); Solution hybridization; Narcotic antagonist; Interaction; Rodentia; Opiates; Gene expression; Opiate receptor μ; Biological activity; Vertebrata; Biological fixation; Mammalia; Mouse; Animal; Antagonist; Irreversible; Mechanism of action
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/0014-2999(95)00488-2

In these experiments, the effect of the irreversible μ-opioid receptor antagonist clocinnamox on the potency of morphine, opioid receptor binding and μ-opioid receptor mRNA was examined. Mice were injected with clocinnamox (0.32–12.8 mg/kg) and the analgesic potency of morphine was examined 24 h later. Clocinnamox produced a dose-dependent decrease in the potency of morphine; and at the higher dose of clocinnamox the maximal analgesic effect was not observed following doses of morphine in excess of 500 mg/kg s.c. In saturation binding studies in brain, clocinnamox (0.32–25.6 mg/kg) dose-dependently decreased μ-opioid ([ 3H][ d-Ala 2,MePhe 4,Gly-ol 5]enkephalin; DAMGO) receptor B max with relatively minimal effects on K d. Binding to δ-opioid receptor ([ 3H][ d-Pen 2, d-Pen 5]enkephalin; DPDPE) and κ-opioid receptor ([ 3H](5,7,8)-(−)- N-methyl- N-(7-(1-pyrrolidinyl)-1-oxaspiro(4,5)dec-8-yl) benzeneacetamide; U69,593) was not affected by clocinnamox. The effect of clocinnamox was time-dependent in that the greatest changes in morphine potency and μ-opioid receptor density were observed within 24 h of administration and decreased with time (336 h). Although μ-opioid receptor density was decreased to less than 30% of control 24 h following clocinnamox (12.8 mg/kg) and had increased to 80% by 5 days, a solution hybridization assay for μ-opioid receptor mRNA transcript revealed no changes in the steady-state levels of this mRNA. These studies indicate that clocinnamox is an irreversible antagonist at the μ-opioid receptor since it appears to selectively affect receptor density with minimal effects on affinity. Furthermore, clocinnamox produces time- and dose-dependent changes in B max and these changes appear to be unrelated to changes in μ-opioid receptor mRNA. It is possible that the repopulation of brain by μ-opioid receptors following clocinnamox is mediated by an existing pool of receptors that are activated following treatment.