Spinal ERK2 activation through δ2-opioid receptors contributes to nociceptive behavior induced by intrathecal injection of leucine-enkephalin.
Intrathecal (i.t.) injection of leucine-enkephalin (Leu-ENK), co-administered with peptidase inhibitors, phosphoramidon (an endopeptidase 24.11 inhibitor), and bestatin (a general aminopeptidase inhibitor), produced behaviors consisting of the biting and/or licking of the hindpaw and the tail along with hindlimb scratching directed toward the flank, which peaked at 10-15 min after an injection. This characteristic behavior was not observed in mice treated with i.t. Leu-ENK alone. We also investigated the effect of the extracellular signal-regulated kinase (ERK) in spinal processing of nociception induced by i.t. co-administration of Leu-ENK with phospharamidon and bestatin. Western blot analysis of phospho-ERK (pERK) showed a significant increase of pERK2 in the lumbar spinal cord in response to i.t. Leu-ENK co-injected with peptidase inhibitors. The MAP kinase-ERK inhibitor, U0126 dose-dependently attenuated the nociceptive behavior and spinal ERK activation to i.t. Leu-ENK co-injected with peptidase inhibitors. Furthermore, the nociceptive behavior and spinal ERK activation evoked by i.t. Leu-ENK in combination with peptidase inhibitors were inhibited by co-administration of the non-selective δ-opioid receptor antagonist, naltrindole, the selective δ2-opioid receptor antagonist, naltriben, the non-competitive N-methyl-D-aspartate (NMDA) antagonist, MK-801 or the non-selective nitric oxide synthase inhibitor, L-NAME, the selective nNOS inhibitor, N(ω)-propyl-L-arginine or the selective iNOS inhibitor, W1400, but not by the selective δ1-receptor antagonist, BNTX (7-benzylidenenaltrexone). These results suggest that spontaneous nociceptive behaviors produced by i.t. co-administration of Leu-ENK with peptidase inhibitors may be induced by an activation of the glutamate-NO-ERK pathway through the δ2-opioid receptor in the dorsal spinal cord.
Department of Pharmacology, Daiichi College of Pharmaceutical Sciences, 22-1 Tamagawa-cho, Minami-ku, Fukuoka 815-8511, Japan.
Takaaki
T
Komatsu
Department of Clinical Pharmaceutics, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan.
Soh
S
Katsuyama
Department of Physiology and Anatomy, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan.
Hirokazu
H
Mizoguchi
Department of Biochemistry, Nihon Pharmaceutical University, 10281 Komuro, Ina-Machi, Kitaadachi-gun, Saitama 362-0806, Japan.
Chikai
C
Sakurada
Department of Biochemistry, Nihon Pharmaceutical University, 10281 Komuro, Ina-Machi, Kitaadachi-gun, Saitama 362-0806, Japan.
Minoru
M
Tsuzuki
Department of Physiology and Anatomy, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan.
Shinobu
S
Sakurada
Department of Pharmacology, Daiichi College of Pharmaceutical Sciences, 22-1 Tamagawa-cho, Minami-ku, Fukuoka 815-8511, Japan. Electronic address: tsukasa@daiichi-cps.ac.jp.
Tsukasa
T
Sakurada
D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D002070:Butadienes / Q000494:pharmacology; D004743:Enkephalin, Leucine / Q000008:administration & dosage / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D006020:Glycopeptides / Q000494:pharmacology; D007278:Injections, Spinal; D007930:Leucine / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D008815:Mice, Inbred Strains; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D009570:Nitriles / Q000494:pharmacology; D059225:Nociception / Q000187:drug effects*; D011480:Protease Inhibitors / Q000494:pharmacology; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D017465:Receptors, Opioid, delta / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013116:Spinal Cord / Q000187:drug effects* / Q000378:metabolism
D002070:Butadienes; D006020:Glycopeptides; C109599:N(omega)-propylarginine; D009570:Nitriles; D011480:Protease Inhibitors; D016194:Receptors, N-Methyl-D-Aspartate; D017465:Receptors, Opioid, delta; C113580:U 0126; D004743:Enkephalin, Leucine; D009271:Naltrexone; D001120:Arginine; D019001:Nitric Oxide Synthase; D019950:Mitogen-Activated Protein Kinase 1; C055382:naltrindole; D007930:Leucine; C012211:ubenimex; C008890:phosphoramidon; D019331:NG-Nitroarginine Methyl Ester
Dorsal spinal cord; Extracellular signal-regulated kinase (ERK); Glutamate; Leucine-enkephalin; Mice; Nitric oxide (NO); Nociceptive behavior; δ(2)-Opioid receptor