title: Intrathecal morphine-3-glucuronide-induced nociceptive behavior via Delta-2 opioid receptors in the spinal cord.
abstract: Intrathecal (i.t.) injection of morphine-3-glucuronide (M3G), a major metabolite of morphine without analgesic actions, produces severe hindlimb scratching followed by biting and licking in mice. The M3G-induced behavioral response was inhibited dose-dependently by pretreatment with an antisera against dynorphin. However, the selective κ-opioid receptor antagonist, nor-BNI did not prevent the M3G-induced behavioral response. Dynorphin is rapidly degraded by a dynorphin-converting enzyme (cystein protease), to leucine-enkephalin (Leu-ENK). The M3G-induced behavioral response was inhibited dose-dependently by pretreatment with the antisera against Leu-ENK. We also showed that M3G co-administered with Leu-ENK-converting enzyme inhibitors, phosphoramidon and bestatin produced much stronger behavioral responses than M3G alone. Furthermore, the M3G-induced behavioral responses were inhibited dose-dependently by i.t. co-administration of the non-selective δ-opioid receptor antagonist, naltrindole or the selective δ2-opioid receptor antagonist, naltriben, whereas the selective δ1-opioid receptor antagonist, BNTX had no effect. An i.t. injection of M3G also produced a definite activation of ERK in the lumbar dorsal spinal cord. Western blotting analysis revealed that antisera against dynorphin, antisera against Leu-ENK, naltrindole or naltriben resulted in a significant blockade of ERK activation induced by M3G in the spinal cord. Taken together, these results suggest that M3G-induced nociceptive responses and ERK activation may be triggered via δ2-opioid receptors activated by Leu-ENK, which is formed from dynorphin in the spinal cord.
authors.affiliation: Department of Pharmacology, Daiichi University of Pharmacy, 22-1 Tamagawa-cho, Minami-ku, Fukuoka, Fukuoka 815-8511, Japan; School of Pharmacy, Duquesne University, 600 Forbes Avenue, Pittsburgh, PA 15282, USA.
authors.forename: Takaaki
authors.initials: T
authors.lastname: Komatsu
authors.affiliation: Center for Experiential Pharmacy Practice, Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan.
authors.forename: Soh
authors.initials: S
authors.lastname: Katsuyama
authors.affiliation: Department of Medicinal Chemistry, Life Science Center of Tsukuba Advanced Research Alliance, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8577, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nagase
authors.affiliation: Department of Physiology and Anatomy, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Mizoguchi
authors.affiliation: Department of Biochemistry, Nihon Pharmaceutical University, 10281 Komuro Ina-Machi Kitaadachi-gun, Saitama 362-0806, Japan.
authors.forename: Chikai
authors.initials: C
authors.lastname: Sakurada
authors.affiliation: Department of Biochemistry, Nihon Pharmaceutical University, 10281 Komuro Ina-Machi Kitaadachi-gun, Saitama 362-0806, Japan.
authors.forename: Minoru
authors.initials: M
authors.lastname: Tsuzuki
authors.affiliation: Department of Physiology and Anatomy, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan.
authors.forename: Shinobu
authors.initials: S
authors.lastname: Sakurada
authors.affiliation: Department of Pharmacology, Daiichi University of Pharmacy, 22-1 Tamagawa-cho, Minami-ku, Fukuoka, Fukuoka 815-8511, Japan. Electronic address: tsukasa@daiichi-cps.ac.jp.
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Sakurada
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D000697:Central Nervous System Stimulants / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004399:Dynorphins / Q000378:metabolism / Q000494:pharmacology; D004743:Enkephalin, Leucine / Q000037:antagonists & inhibitors / Q000378:metabolism; D007278:Injections, Spinal; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D051379:Mice; D009022:Morphine Derivatives / Q000008:administration & dosage / Q000494:pharmacology*; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D059225:Nociception / Q000187:drug effects*; D017465:Receptors, Opioid, delta / Q000187:drug effects*; D013116:Spinal Cord / Q000187:drug effects*
chemical_list: D000697:Central Nervous System Stimulants; D009022:Morphine Derivatives; D009292:Narcotic Antagonists; D017465:Receptors, Opioid, delta; C051844:norbinaltorphimine; D004743:Enkephalin, Leucine; D009271:Naltrexone; D004399:Dynorphins; C018108:morphine-3-glucuronide
keywords: Dorsal spinal cord; Dynorphin; Extracellular signal-regulated kinase (ERK); Leucine-enkephalin; Mice; Morphine-3-glucuronide (M3G); δ(2)-opioid receptor