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The role of the hydrophilic Asn230 residue of the mu-opioid receptor in the potency of various opioid agonists.

ABSTRACT: 1. To investigate the effect of the hydrophilic Asn amino acid at position 230 of the human mu-opioid receptor (hMOR230) on the potency of various agonists, we mutated this residue to Thr and Leu (hMORN230T and hMORN230L respectively). 2. Taking advantage of the functional coupling of the opioid receptor with the heteromultimeric G-protein-coupled inwardly rectifying K(+) (GIRK1/GIRK2) channel, either the wild type hMOR or one of the mutated receptors (hMORN230L or hMORN230T) were functionally coexpressed with GIRK1/GIRK2 channels and a regulator of G-protein signalling (RGS4) in Xenopus laevis oocytes. 3. The two-microelectrode voltage clamp technique was used to measure the opioid receptor-activated GIRK1/GIRK2 channel responses. The potency of [D-Ala(2),N-MePhe(4),Gly(5)-ol]-enkephalin (DAMGO), remained unaffected as measured via hMORN230T and hMORN230L, while the potency of fentanyl and morphine significantly increased via these mutated receptors. 4. Our results are indicative for the existence of hydrophobic interactions between a methyl-group of the side chain of Thr or Leu on the one hand and the piperidine-ring of fentanyl and the hexene-ring of morphine on the other. The mutations also had no influence on the potency of morphine-6-glucuronide (M6G) and morphine-3-glucuronide (M3G). 5. We conclude that the hydrophilic side chain of Asn in position 230 is not involved in the formation of a H-bond with the aliphatic alcohol of morphine and that an enhancement of the potency of morphine and fentanyl can be explained by mutating this residue towards more hydrophobic amino acids.

SUBMITTER: Pil J

PROVIDER: S-EPMC1572970 | biostudies-other | 2001 Oct

REPOSITORIES: biostudies-other

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Project description:Mu-opioid receptor agonists are clinically effective analgesics, but also produce undesirable effects that limit their clinical utility. The nociceptin opioid peptide (NOP) receptor system also modulates nociception, and NOP agonists might be useful adjuncts to enhance the analgesic effects or attenuate the undesirable effects of mu-opioid agonists. The present study determined behavioral interactions between the NOP agonist (-)-Ro 64-6198 and mu-opioid ligands that vary in mu-opioid receptor efficacy (17-cyclopropylmethyl-3,14β-dihyroxy-4,5α-epoxy-6α-[(3 ́-isoquinolyl)acetamindo]morphinan (NAQ) < buprenorphine < nalbuphine < morphine = oxycodone < methadone) in male rhesus monkeys. For comparison, Ro 64-6198 interactions were also examined with the kappa-opioid receptor agonist nalfurafine. Each opioid ligand was examined alone and following fixed-dose Ro 64-6198 pretreatments in assays of thermal nociception (n = 3-4) and schedule-controlled responding (n = 3). Ro 64-6198 alone failed to produce significant antinociception up to doses (0.32 mg/kg, IM) that significantly decreased rates of responding. All opioid ligands, except NAQ and nalfurafine, produced dose- and thermal intensity-dependent antinociception. Ro 64-6198 enhanced the antinociceptive potency of buprenorphine, nalbuphine, methadone, and nalfurafine. Ro 64-6198 enhancement of nalbuphine antinociception was NOP antagonist SB-612111 reversible and occurred under a narrow range of dose and time conditions. All opioid ligands, except NAQ and buprenorphine, produced dose-dependent decreases in rates of responding. Ro 64-6198 did not significantly alter mu-opioid ligand rate-decreasing effects. Although these results suggest that NOP agonists may selectively enhance the antinociceptive vs. rate-suppressant effects of some mu-opioid agonists, this small enhancement occurred under a narrow range of conditions dampening enthusiasm for NOP agonists as candidate "opioid-sparing" adjuncts.

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The role of the hydrophilic Asn230 residue of the mu-opioid receptor in the potency of various opioid agonists.

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