title: The spinal antinociceptive mechanism determined by systemic administration of BD1047 in zymosan-induced hyperalgesia in rats.
abstract: Although sigma-1 receptor (Sig-1R) antagonists have a potential antinociceptive effect in inflammatory diseases, the precise mechanism is not fully understood. The present study was aimed to elucidate the role of spinal neurons and microglia in the anti-nociceptive mechanism of BD1047 (a prototypical Sig-1R antagonist) using an inflammatory pain model based on intraplantar injection of zymosan. Oral pretreatment with BD1047 dose-dependently reduced zymosan-induced thermal and mechanical hyperalgesia as well as spinal neuronal activation including increased immunoreactivity of Fos, protein kinase C (PKC) and 'PKC-dependent phosphorylation of the NMDA receptor subunit 1' (pNR1). Zymosan also led to increased CD11b immunoreactivity (a marker of microglia) accompanied by 'phosphorylated p38 mitogen activated protein kinase' (p-p38MAPK) and interleukin-1βimmunoreactivity in the spinal dorsal horn. Intrathecal injection of a microglia modulator (minocycline), p38MAPK inhibitor (SB203580) or interleukin-1βneutralizing antibody significantly attenuated zymosan-induced hyperalgesia. Specifically, oral pretreatment with BD1047 reduced the immunoreactivity of CD11b, p-p38MAPK and interleukin-1β. In the spinal cord section, Sig-1R immunoreactivity was exclusively distributed in both spinal dorsal horn neurons and central endings of unmyelinated primary afferent fibers but not in glia. Intrathecal injection of BD1047 alleviated zymosan-induced hyperalgesia up to the level of oral administration. Taken together, our data imply that antinociceptive effect induced by oral treatment with BD1047 may be mediated, at least in part, by the inhibition of neuronal and microglial activation in the spinal cord triggered by inflammatory conditions.
authors.affiliation: Department of Pharmacology, Institute for Medical Science, Chonbuk National University Medical School, Jeonju, Republic of Korea.
authors.forename: Young Chan
authors.initials: YC
authors.lastname: Jeong
authors.affiliation: Department of Anesthesiology and Pain Medicine, Research Institute of Clinical Medicine of Chonbuk National University, Biomedical Research Institute of Chonbuk National University Hospital, Jeonju, Republic of Korea.
authors.forename: Ji Seon
authors.initials: JS
authors.lastname: Son
authors.affiliation: Department of Pharmacology, Institute for Medical Science, Chonbuk National University Medical School, Jeonju, Republic of Korea. Electronic address: 1972y@jbnu.ac.kr.
authors.forename: Young Bae
authors.initials: YB
authors.lastname: Kwon
mesh_terms: D000284:Administration, Oral; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D005029:Ethylenediamines / Q000494:pharmacology*; D006930:Hyperalgesia / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008297:Male; D017628:Microglia / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010146:Pain / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D020671:Posterior Horn Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D017207:Rats, Sprague-Dawley; D017480:Receptors, sigma / Q000037:antagonists & inhibitors / Q000378:metabolism; D013116:Spinal Cord / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D015054:Zymosan
chemical_list: D000700:Analgesics; D000893:Anti-Inflammatory Agents; D005029:Ethylenediamines; D017480:Receptors, sigma; C097963:N-(2-(3,4-Dichlorphenyl)ethyl)-N,N',N'-trimethyl-1,2-ethandiamin; D015054:Zymosan
keywords: Hyperalgesia; Interleukin-1β; Microglia; Mitogen activated protein kinase (MAPK); Sigma-1 receptor (Sig-1R); Zymosan