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Intrathecal administration of sigma‐1 receptor agonists facilitates nociception: Involvement of a protein kinase C–dependent pathway
Author(s) -
Roh DaeHyun,
Kim HyunWoo,
Yoon SeoYeon,
Seo HyoungSig,
Kwon YoungBae,
Kim KeeWon,
Han HoJae,
Beitz Alvin J.,
Lee JangHern
Publication year - 2008
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/jnr.21802
Subject(s) - nociception , protein kinase c , sigma 1 receptor , chelerythrine , pharmacology , sigma receptor , chemistry , receptor , opioid receptor , agonist , signal transduction , medicine , biochemistry
Sigma sites, originally proposed as opioid receptor subtypes, are currently thought to represent unique receptors with a specific pattern of drug selectivity, a well‐established anatomical distribution and broad range of functional roles including potential involvement in nociceptive mechanisms. We have recently demonstrated that intrathecal (i.t.) treatment with a sigma‐1 receptor antagonist reduced formalin‐induced pain behavior. In the present study, we investigated the potential role of spinal sigma‐1 receptor agonists in peripherally initiated nociception and attempted to elucidate intracellular signaling mechanisms associated with spinal cord sigma‐1 receptor activation in mice. The i.t. injection of the sigma‐1 receptor agonists PRE‐084 (PRE) or carbetapentane (CAR) significantly decreased tail‐flick latency (TFL) and increased the frequency of paw withdrawal responses to mechanical stimulation (von Frey filament, 0.6 g) as well as the amount of Fos expression in the spinal cord dorsal horn induced by noxious paw‐pinch stimulation. These PRE‐ or CAR‐induced facilitatory effects on nociception were significantly blocked by i.t. pretreatment with the sigma‐1 receptor antagonist, BD‐1047, the phospholipase C (PLC) inhibitor, U‐73,122, the Ca 2+ ‐ATPase inhibitor, thapsigargin, and the protein kinase C (PKC) inhibitor, chelerythrine. Western blot analysis further revealed that i.t. PRE or CAR injection significantly increased pan‐PKC as well as the PKCα, ϵ, and ζ isoforms in the dorsal horn. Collectively, these findings demonstrate that calcium‐dependent second messenger cascades including PKC are involved in the facilitation of nociception associated with spinal sigma‐1 receptor activation. © 2008 Wiley‐Liss, Inc.