| Co-Investigator(Kenkyū-buntansha) |
NAKAGAWA Takayuki Kyoto University, Faculty of Pharmaceutical Sciences, Instructor, 薬学研究科, 助手 (30303845)
NAGASE Hiroshi Toray Industries, Inc., Basic Research Laboratory, Chief Research Fellow, 基礎研究所・創薬研究室, 室長
MINAMI Masabumi Kyoto University, Faculty of Pharmaceutical Sciences, Assistant Professor, 薬学研究科, 助教授 (20243040)
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| Research Abstract |
The nociceptin receptor was firstly cloned as an opioid receptor-like orphan receptor. Recently, nociceptin (orphanin FQ) has been isolated as an endogenous peptidic ligands of this orphan receptor, but the physiological and pathological roles of nociceptin have not been elucidated.
To obtain useful information about creating nonpeptidic ligands of the nociceptin receptor, we investigated the molecular mechanism of the discrimination by bremazocine, a nonpeptidic opioid ligand, between opioid receptors and nociceptin receptor, by constructing chimeric and mutated nociceptin receptors. We revealed that the difference of four residues between Ala^<216>, Val^<279>, and Val^<281> of nociceptin receptor and Lys^<227>, Ile^<290>, His^<291> and Ile^<292> of k-opioid receptor is critical for the discrimination by bremazocine.
Furthermore, we established a system to evaluate the agonistic and antagonistic activity for the nociceptin receptor. Using this system, we examined the agonistic and antag
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onistic activity of several nonpeptidic opioid ligands for the nociceptin receptor. TRK-820 and naloxone benzoylhydrazone showed antagonistic activities for the nociceptin receptor at relatively high concentrations. In this system, we demonstrated that [Phe^1PSI(CH_2-NH)Gly^2]nociceptin(1-13)NH_2, which has been reported as a peptidic nociceptin receptor-selective antagonist, is a partial agonist/antagonist of the nociceptin receptor.
We also investigated the in vivo effect of [Phe^1PSI(CH2-NH)Gly2]nociceptin(1-13)NH2 in mice. Intrathecal (i.t.) administration of nociceptin and [Phe^1PSI(CH_2-NH)Gly^2]nociceptin(1-13)NH_2 produced similar responses, such as licking, biting and scratching at low doses. In addition, both ligands displayed bidirectional effects on formalin-induced aversive responses depending on the doses. Intrathecal adrninistration of [Phe^1PSI(CH_2-NH)Gly^2]nociceptin(1-13)NH_2 reduced the behavioral responses induced by nociceptin. These results indicated that [Phe^1PSI(CH_2-NH)Gly^2]nociceptin(1-13)NH_2 acts as a mixed agonist/antagonist of the nociceptin receptor both in vitro and in vivo. Less
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