オピオイドμ-1受容体にさらなるサブタイプの存在の可能性

• 研究課題/領域番号: 12672220
• 研究種目: 基盤研究(C)
• 配分区分: 補助金
• 応募区分: 一般
• 研究分野: 応用薬理学・医療系薬学
• 研究機関: 東北薬科大学
• 研究代表者: 櫻田 忍 東北薬科大学, 薬学部, 教授 (30075816)
• 研究期間 (年度): 2000 – 2003
• 研究課題ステータス: 完了 (2003年度)
• 配分額: 3,500千円 (直接経費: 3,500千円); 2003年度: 500千円 (直接経費: 500千円); 2002年度: 600千円 (直接経費: 600千円); 2001年度: 900千円 (直接経費: 900千円); 2000年度: 1,500千円 (直接経費: 1,500千円)
• キーワード: μopioid / μ1受容体 / endomorphin-1 / endomorphin-2 / dynorphinA(1-17) / naloxonazine / β-funaltrexamine / Met-enkephalin / D-Pro-endomorphin-1 / D-Pro-endomorphin-2 / DAMGO / μ opioid / 3-methoxynaltorexone

研究概要

Opioidμ受容体は生化学的及び薬理学的見地から、少なくとも2つ以上のsubtypeの存在が推測されている。これまでμ1受容体拮抗薬であるnanoxonazinc及びμ1及びμ2受容体拮抗薬であるβ-funaltrexamineを用いてμ受容体のsubtypeを決定する方法が用いられている。これまでμ2受容体の特異的拮抗薬は発見されていなかったが、著者の研究によってD-Pro^2-endomorphin-1が特異的な拮抗薬であることが見出された。μ2 agonistであるDAMGO及びendomorphin-1の拮抗作用は、D-Pro^2-endomorphinの併用により拮抗することが認められた。さらにD-Pro^2-endomorphin-2はDAMGO及びendomorphin-1の抗侵害作用には拮抗しなかった(Br.J.Pharmacol.137,1143-1146)。これまでの著者の研究から、TAPA (Tyr-D-Arg-Phe-β-Ala)はnaloxonazineに対して高感受性であり、μ1受容体agonistであることが認められた(Eur.J.Pharmacol.,486,19-24(2004))。TAPAによって引き起こされる抗侵害作用はD-Pro^2-endomorphin-2によって拮抗されたことから、D-Pro^2-endomorphin-1はμ2受容体及びD-Pro^2-endomorphin-1はμ2受容体及びD-Pro^2-endomorphin-2はμ1受容体拮抗薬であることが示されたのである。これらμ受容体のsubtypeの分類はμ受容体の種々の作用を分類できるのみならず、副作用のない強力な鎮痛作用を検討する上で重要な指針となるであろう。

研究成果

• [文献書誌] Shinobu Sakurada: "Synthesis and structure-activity relationships of an orally-available and long-acting analgesic peptide, α-amidino-Tyr-D-Arg-Phe-Me β Ala-OH (ADAMB)"J.Med.Chem.. 45. 5081-5089 (2002)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] Shinobu Sakurada: "Endomorphin analogues containing D-Pro^2 discriminate different μ-opioid receptor mediated antinociception in mice"Brit.J.Pharmacol.. 137. 1143-1146 (2002)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] Shinobu Sakurada: "D-Pro^2-andomorphin-1 and D-Pro^2-endomorphin-2, respectively, attenuate the antinociception induced by encomorphin-1 and endomorphin-2 given intrathecally in the mouse"J.Pharmacol.Exp.Ther.. 303. 874-879 (2002)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] Shinobu Sakurada: "Blood-brain barrier transport of a novel μ1-specific opioid peptide, H-Tyr-D-Arg-Phe-β-Ala-OH(TAPA)"J.Neurochem. 84. 1154-1161 (2003)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] Shinobu Sakurada: "Differential involvement of μ1-opioid receptor in dermorphin tetrapeptide analogues-induced antinociceptin"Eur.J.Pharmacol.. 486. 19-24 (2004)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] Tsukasa Sakurada, Masayuki Yuhki, Makoto Inoue, Chikai Sakurada, Koichi Tan-No, Masataka Obba, Kensuke Kisara, Shinobu Sakurada: "Opiold activity of sendide, a tachykinin NJC1 receptor antagonist"European Journal of Pharmacology. 369. 261-266 (1999)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Shinobu Sakurada, James E.Zadina, Abba J.Kastin, Sou Katsuyama, Tsutomu Fujimura, Kimie Murayama, Masayuki Yuki, Hiroshi Ueda, Tsukasa Sakurada: "Differential involvement of μ-opioid receptor subtypes in endomorphin-1-and -2-induced antinociception"European Journal of Pharmacology. 372. 25-30 (1999)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] O.Nakagawasai, T.Tadano, K.Tan-No, F.Nuijinia, S.Sakurada, Y.Endo, K.Kisara: "Changes in β-Endorphin and Stress-Induced Analgesia in Mice After Exposure to Forced Walking Stress"Methods Find.ExClin.Pharmacol.. 21. 471-476 (1999)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Fukie Niijima.Koichi Tan-No, Akihisa Esashi, Osamu Nakagawasai, Takeshi Tadano, Norio Takahashi, Akihiko Yonezawa, Shinobu Sakurada, Kensuke Kisara: "Inhibitory effect of intracerebroventricularly-admninistered [D-Arg^2,β-Ala^4]-dermorphin (1-4) on gastrointestinal transit"Pepties. 21. 295-299 (2000)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Shinobu Sakurada, Satoshi Takeda, Takumi Sato, Takafumi Hayashi, Masayuki Yuki, Motoharu Kutsuwa, Koichi Tan-No, Chikai Sakurada, Kensuke Kisara, Tsukasa Sakurada: "Selective antagonism by naloxonsaine of antinoclception by Tyr-D-Arg-Phe-p-AIa, a novel dermorphin analogue with high affinity at μ-opioid receptors"European Journal of Pharmacology. 395. 107-112 (2000)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Shinobu Sakurada, Takafumi Hayashi, Masayuki Yuhki, Tsutomu Fujimura, Kimie Murayama, Akihiko Yonezawa, Chikai Sakurada, Mitsuhiro Takeshita, James E.Zadina, Abba I.Kastin, Taukasa Sakurada: "Differential antagonism of endomorphin-1 and endomorphin-2 spinal antinociception by naloxonazins and 3-mnethoxynaltrexone"BRAIN RESEARCH. 881. 1-8 (2000)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Shinobu Sakurada, Takafumi Haysahi, Masayuki Yuhki, Tohru Onto, James E.Zadina, Abba I.Kastin, Tsutomu Fujimura, Kimie Murayama, Chikai Sakurada, Tsukasa Sakurada, Minoni Narita, Tsutomu Suzuki, Koichi Tan-no, Leon F.Tseng: "Differential antinociceptive effects induced by intrathecatly administered endomorphin-I and endomorpbin-2 in the mouse"European Journal of Pharmacology. 472. 203-210 (2001)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Tadashi Ogawa, Tetauhisa Miyamae, Toni Okayama, Masaki Hagiwara, Shinobu Sakurada, Tadanori Morikawa: "Structure-Activity Relationships (SAR) of [D-Arg Analogues, N-Amidino-Tyr-D-Arg-Phe-X"Chem.Pharm.Bull.. 50. 771-780 (2002)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Minoru Narita, Shinobu Sakurada: "Recent Advances In the Search for the μ-OpioidergiF System"Jpn.J.Pharmacol.. 89. 201-202 (2002)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Shinobu Sakurada, Takafumi Hayashi, Masayuki Yuhki: "Differential Antinociceptive Effects Induced by Intrathecally. Admlnistered Endomorphin-1 and Endomorphin-2 in Mice"Jpn.J.Pharmacol. 90. 221-223 (2002)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Shinobu Sakurada, Takafumi Hayashi, Masayuki Yuhki, Tsutomu Fujimura, Kimie Murayama, Akihiko Yonezawa, Oiikai Sakurada, Mitauhiro Takeshita, Takumi Sato, James B.Zadina, Abba J.Kastin, Tsukasa Sakurada: "Differential antagonism of endomorphin-1 and endomorphin-2 supraspinal antinociception by naloxonazine and 3-methylnaltzexone"Peptides. 23. 895-901 (2002)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Kuei-Chung Hung, Hsiang-En Wu, Hirokazu Mizoguchi, Shinobu sakurada, Torii Okaysma, Tsutomu Fujimura, Kimie Murayama, Tsukasa Sakurada, James M.Fujimoto, Leon F.Tseng: "D-Pro^2-Endomorphin-1 and D-Pro^2-Endomorphin-2 Respectively, Attenuate the Antinociception Induced by Endomorphln-1 and Endomorphin-2 Given Intrathecatly in the Mouse"J.Pharmacol.ExTher.. 303. 874-879 (2002)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Shinobu Sakurada, Hiroyuki Watanabe, Takafumi Hayashi, Masayuki Yuhki, Tsutomu Fujimura, Kimie Maruyama, Chikai Sakurada, Tsukasa Sakurada: "Endomorphin analogues containing D-Pro^2 different μ-opioid receptor mediated antinociception in mice"British Journal Pharmacology. 137. 1143-1146 (2002)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Yoshiharu Deguchi, Yusaku Miyakawa, Shinobu Sakurada, Yu Naito, Kazuhiro Morimoto, Sumio Ohtsuki, Ken-ichi Hosoya, Tetsuya Terasaki: "Blood-brain barrier transport of a novel 1&,-specific opioid peptide, H-Tyr-D-Arg-Phe-β-Ala-0H (TAPA)"Journal of Meurochemistry. 84. 1154-1161 (2003)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Chikai Sakurada, Shinobu Sakurada, Takafumi Hayashi, Sou Katsuyama, Koichi Tan-No, Tsukasa Sakurada: "Degradation of endomorphin-2 at the supraspinal level in mice is initiated by dipeptidyl peptidase IV: an in vitro and in vivo study"Biochemical Pharmacology. 66. 653-661 (2003)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Hirokazu Mizoguchi, Masayuki Yuhki, Hiroyuki Watanabe, Takafumi Hayashi, Chikai Sakurada, Akihiko Yonezawa, Tsukasa Sakurada, Shinobu Sakurada: "Differential involvement of μ_1 receptor on dermorphin tetrapeptide analogues-induced antinociception"European Journal of Pharmacology. 486. 19-24 (2004)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Shinobu Sakurada: "Synthesis and structure-activity relationships of an orally-available and long-acting analgesic peptide, α- amidino-Tyr-D-Arg-Phe-Me β Ala-OH (ADAMB)"J.Med.Chem.. 5081-5089 (2002)
• [文献書誌] Shinobu Sakurada: "Endomorphin analogues containing D-Pro^2 discriminate different μ-opioid receptor mediated antinociception in mice"Brit.J.Pharmacol. 1143-1146 (2002)
• [文献書誌] Shinobu Sakurada: "Differential antagonism of endomorphin-1 and endmorphin-2 supraspinal antinociception by naloxonazine and 3-methylnaltrexone"Peptides. 895-901 (2002)
• [文献書誌] Shinobu Sakurada: "D-Pro^2-endomorphin-1 and D-Pro^2-endmorphin-2, respectively, attenuate the antinociception induced by endomorphin-1 and endomorphin-2 given intrathecally in the mouse"J.Pharmacol.Exp.Ther. 874-879 (2002)
• [文献書誌] Shinobu Sakurada: "Blood-brain barrier transport of a novel μ1-specific opioid peptide, H-Tyr-D-Arg-Phe-β- Ala-OH(TAPA)"J.Neurochem. 1154-1161 (2003)
• [文献書誌] Shinobu Sakurada: "Differential involvement of μ1-opioid receptor in dermorphin tetrapeptide analogues-induced antinociception"Eur.J.Pharmacol. 19-24 (2004)
• [文献書誌] Shinobu Sakurada: "Synthesis and structure-activity relationships of an orally-available and long-acting analgesic peptide, N^α-amidino-Tyr-D-Arg-Phe-MeβAla-OH (ADAMB)"J. Med. Chem. 45. 5081-5089 (2002)
• [文献書誌] Shinobu Sakurada: "Endomorphin analogues containing D-Pro^2 discriminate different μ-opiod receptor mediated antinociception in mice"Brit. J. Pharmacol. 137. 1143-1146 (2002)
• [文献書誌] Shinobu Sakurada: "Structure-activity relationships (SAR) of [D-Arg^2]dermorphin(1-4) analogues, N^α-amidino-Tyr-D-Arg-Phe-X"Chem. Pharm. Bull. 50. 771-780 (2002)
• [文献書誌] Shinobu Sakurada: "Differential antagonism of endomorphin-1 and endmorphin-2 supraspinal antinociception by naloxonazine and 3-methylnaltrexone"Peptides. 23. 895-901 (2002)
• [文献書誌] Shinobu Sakurada: "D-Pro^2-endomorphin-1 and D-Pro^2-endomorphin-2, respectively, attenuate the anitinociception induced by endomorphin-1 and endomorphin-2 given intrathecally in the mouse"J. Pharmacol. Exp. Ther. 303. 874-879 (2002)
• [文献書誌] Shinobu Sakurada: "Blood-brain barrier transport of a novel μ_1-specific opioid peptide, H-Tyr-D-Arg-Phe-β-ala-OH (TAPA)"J. Neurochem. 84. 1154-1161 (2003)
• [文献書誌] Takumi Sato: "Contribution of spinal μ1-opioid receptors to morphine-induced antinociception."Eur. J. Pharmacol. 369. 183-187 (1999)
• [文献書誌] Shinobu Sakurada: "Differential involvement of μ-opioidreceptor subtype in endomorphin-1 and -2-induced antinociception."Eur. J. Pharmacol. 372. 25-30 (1999)
• [文献書誌] Shinobu Sakurada: "Selective antagonism by naloxonazine of antinociception by Tyr-D-Arg-Phe-β-Ala, novel dermorphin analogue with high affinity at μ-opioidreceptors."Eur. J. Pharmacol. 395. 107-112 (2000)
• [文献書誌] Shinobu Sakurada: "Differential antagonism of endomorphin-1 and endomorphin-2 spinal antinociception by naloxonazine and 3-methoxynaltrexone."Brain Research. 881. 1-8 (2000)
• [文献書誌] Shinobu Sakurada: "Differential antinociceptive effects induced by intrathecally dministered endomorphin-1 and endomorphin-2"Eur. J. Pharmacol. 427. 203-210 (2001)
• [文献書誌] Takumi Sato: "Contribution of spinal μ1-opioid receptors to morphine-induced antinociception."Eur.J.Pharmacol. 369. 183-187 (1999)
• [文献書誌] Shinobu Sakurada: "Differential involvement of μ-opioidreceptor subtype in endomorphin-1 and 2-induced antinociception."Eur.J.Pharmacol.. 372. 25-30 (1999)
• [文献書誌] Shinobu Sakurada: "Selective antagonism by naloxonazine of antinociception by Tyr-D-Arg-Phe-β-Ala, novel dermorphin analogue with high affinity at μ-opioidreceptors."Eur.J.Pharmacol. 395. 107-112 (2000)
• [文献書誌] Shinobu Sakurada: "Differential antagonism of endomorphin-1 and endomorphin-2 spinal antinociception by naloxonazine and 3-methoxynaltrexone."Brain Research. 881. 1-8 (2000)