Intrathecal administration of sigma-1 receptor agonists facilitates nociception: Involvement of a protein kinase C-dependent pathway

Dae Hyun Roh, Hyun Woo Kim, Seo Yeon Yoon, Hyoung Sig Seo, Young Bae Kwon, Kee Won Kim, Ho Jae Han, Alvin J. Beitz, Jang Hern Lee

Research output: Contribution to journalArticlepeer-review

32 Scopus citations

Abstract

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 Ca2+-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.

Original languageEnglish (US)
Pages (from-to)3644-3654
Number of pages11
JournalJournal of Neuroscience Research
Volume86
Issue number16
DOIs
StatePublished - Dec 1 2008

Keywords

  • Fos protein
  • Pain
  • Phospholipase C
  • Protein kinase C
  • Sigma-1 receptor

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