title: Pharmacological mechanisms underlying the antinociceptive and tolerance effects of the 6,14-bridged oripavine compound 030418.
abstract: OBJECTIVE
  To investigate possible pharmacological mechanisms underlying the antinociceptive effect of and tolerance to N-methyl-7α-[(R)-1-hydroxy-1-methyl-3-(thien-3-yl)-propyl]-6,14-endo-ethanotetrahydronororipavine (030418), a derivative of thienorphine.
  
  
  METHODS
  The binding affinity and efficacy of 030418 were determined using receptor binding and guanosine 5'-O-(3-[(35)S]thio)triphosphate ([(35)S]GTPγS) assays in CHO-μ, CHO-κ, CHO-δ, and CHO-ORL1 cell membranes. The analgesic activity of and tolerance to 030418 were evaluated in thermal nociceptive tests in mice. The effects of 030418 on opioid receptors were further investigated using in vivo pharmacological antagonist blockade and in vitro tissue preparations.
  
  
  RESULTS
  The compound 030418 displayed high binding affinity to all subtypes of opioid receptors with K(i) values in the nanomolar range. In [(35)S]GTPγS binding assay, the maximal stimulation of 030418 to μ-, κ-, δ-receptors and the ORL1 receptor was 89%, 86%, 67% and 91%, respectively. In hot-plate test, the antinociceptive effect of 030418 was more potent and longer than morphine. The nonselective opioid receptor antagonist naloxone could completely block 030418-induced antinociception, while both the μ-opioid receptor antagonist β-FNA and the κ-opioid receptor antagonist nor-BNI attenuated 030418-induced antinociception. In contrast, the ORL1 receptor antagonist J-113397 enhanced the antinociceptive effect of 030418. Additionally, chronic treatment with 030418 resulted in a dramatic development of tolerance that could not be effectively prevented by J-113397. In guinea pig ileum preparation, the existing action of 030418 could be removed with difficulty after prolonged washing.
  
  
  CONCLUSIONS
  The compound 030418 is a novel agonist of opioid receptors with high efficiency, long-lasting effect and liability to tolerance, which may be closely correlated with the methyl group at the N(17) position and the high hydrophobicity of the C(7)-thiophene group in its chemical structure.
authors.affiliation: Department of Medicine Evaluation, Beijing Institute of Pharmacology and Toxicology, Beijing, China.
authors.forename: Quan
authors.initials: Q
authors.lastname: Wen
authors.forename: Gang
authors.initials: G
authors.lastname: Yu
authors.forename: Yu-lei
authors.initials: YL
authors.lastname: Li
authors.forename: Ling-di
authors.initials: LD
authors.lastname: Yan
authors.forename: Ze-hui
authors.initials: ZH
authors.lastname: Gong
mesh_terms: D000700:Analgesics / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D002047:Buprenorphine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D016466:CHO Cells; D006224:Cricetinae; D004361:Drug Tolerance; D005260:Female; D006168:Guinea Pigs; D008297:Male; D051379:Mice; D059225:Nociception / Q000187:drug effects; D010147:Pain Measurement / Q000187:drug effects*; D011957:Receptors, Opioid / Q000378:metabolism; D013797:Thebaine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000700:Analgesics; D011957:Receptors, Opioid; C512397:thienorphine; D013797:Thebaine; D002047:Buprenorphine; C005283:oripavine