title: Continuous infusion of substance P into rat striatum alleviates nociceptive behavior via phosphorylation of extracellular signal-regulated kinase 1/2.
abstract: Intraplantar injection of 0.4% formalin into the rat hind paw leads to a biphasic nociceptive response; an 'acute' phase (0-15 min) and 'tonic' phase (16-120 min), which is accompanied by significant phosphorylation of extracellular signal-regulated kinase (ERK)1/2 in the contralateral striatum at 120 min post-formalin injection. To uncover a possible relationship between the slow-onset substance P (SP) release and increased ERK1/2 phosphorylation in the striatum, continuous infusion of SP into the striatum by reverse microdialysis (0.4 μg/mL in microdialysis fiber, 1 μL/min) was performed to mimic volume neurotransmission of SP. Continuous infusion for 3 h of SP reduced the duration of 'tonic' phase nociception, and this SP effect was mediated by neurokinin 1 (NK1) receptors since pre-treatment with NK1 receptor antagonist CP96345 (10 μM) blocked the effect of SP infusion. However, formalin-induced 'tonic' phase nociception was significantly prolonged following acute injection of the MAP/ERK kinase 1/2 inhibitor PD0325901 (100 pmol) by microinjection. The coinfusion of SP and PD0325901 significantly increased the 'tonic' phase of nociception. These data demonstrate that volume transmission of striatal SP triggered by peripheral nociceptive stimulation does not lead to pain facilitation but a significant decrease of tonic nociception by the activation of the SP-NK1 receptor-ERK1/2 system. Noxious stimulation induces a slow-onset substance P (SP) release as a volume transmitter, activating extra-synaptic NK1 receptors, and evokes phosphorylation of extracellular signal-regulated kinase (ERK) 1/2. The SP-NK1-ERK1/2 system in the striatum decreases tonic nociception.
authors.affiliation: Department of Pharmacology, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.
authors.forename: Yoki
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Hiroki
authors.initials: H
authors.lastname: Izumi
authors.forename: Ryo
authors.initials: R
authors.lastname: Fukushige
authors.forename: Takumi
authors.initials: T
authors.lastname: Shimizu
authors.forename: Kyohei
authors.initials: K
authors.lastname: Watanabe
authors.forename: Norimitsu
authors.initials: N
authors.lastname: Morioka
authors.forename: Aldric
authors.initials: A
authors.lastname: Hama
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Takamatsu
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Nakata
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D003342:Corpus Striatum / Q000187:drug effects*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D059226:Nociceptive Pain / Q000188:drug therapy*; D010147:Pain Measurement; D010766:Phosphorylation / Q000187:drug effects; D017208:Rats, Wistar; D018040:Receptors, Neurokinin-1 / Q000378:metabolism; D013116:Spinal Cord / Q000187:drug effects; D013373:Substance P / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D009435:Synaptic Transmission / Q000502:physiology
chemical_list: D018040:Receptors, Neurokinin-1; D013373:Substance P; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3
keywords: ERK1/2; anti-nociception; reverse microdialysis; striatum; substance P; volume transmission