1. Spinal ERK2 activation through δ2-opioid receptors contributes to nociceptive behavior induced by intrathecal injection of leucine-enkephalin.
- Author
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Komatsu T, Katsuyama S, Mizoguchi H, Sakurada C, Tsuzuki M, Sakurada S, and Sakurada T
- Subjects
- Animals, Arginine analogs & derivatives, Arginine pharmacology, Behavior, Animal drug effects, Butadienes pharmacology, Enkephalin, Leucine administration & dosage, Enzyme Activation drug effects, Glycopeptides pharmacology, Injections, Spinal, Leucine analogs & derivatives, Leucine pharmacology, Male, Mice, Inbred Strains, NG-Nitroarginine Methyl Ester pharmacology, Naltrexone analogs & derivatives, Naltrexone pharmacology, Nitric Oxide Synthase antagonists & inhibitors, Nitriles pharmacology, Protease Inhibitors pharmacology, Receptors, N-Methyl-D-Aspartate antagonists & inhibitors, Receptors, Opioid, delta antagonists & inhibitors, Spinal Cord metabolism, Enkephalin, Leucine pharmacology, Mitogen-Activated Protein Kinase 1 metabolism, Nociception drug effects, Receptors, Opioid, delta metabolism, Spinal Cord drug effects
- Abstract
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., (Copyright © 2014 Elsevier Inc. All rights reserved.)
- Published
- 2014
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