Sigma-1 receptor-mediated increase in spinal p38 MAPK phosphorylation leads to the induction of mechanical allodynia in mice and neuropathic rats

Ji Young Moon, Dae Hyun Roh, Seo Yeon Yoon, Suk Yun Kang, Sheu Ran Choi, Soon Gu Kwon, Hoon Seong Choi, Ho Jae Han, Alvin J. Beitz, Jang Hern Lee

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34 Scopus citations


The direct activation of the spinal sigma-1 receptor (Sig-1R) produces mechanical allodynia (MA) and thermal hyperalgesia (TH) in mice. In addition, the blockade of the spinal Sig-1R prevents the induction of MA, but not TH in chronic constriction injury (CCI)-induced neuropathic rats. The present study was designed to investigate whether the increase in spinal p38 MAPK phosphorylation (p-p38 MAPK) mediates Sig-1R-induced MA or TH in mice and the induction of MA in neuropathic rats. MA and TH were evaluated using von Frey filaments and a hot-plate apparatus, respectively. Neuropathic pain was produced by CCI of the right sciatic nerve in rats. Western blot assay and immunohistochemistry were performed to determine the changes of p-p38 MAPK expression in the spinal cord. Intrathecal (i.t.) injection of PRE084, a selective Sig-1R agonist, into naïve mice time-dependently increased the expression of p-p38 MAPK, which was blocked by pretreatment with BD1047, a Sig-1R antagonist. I.t. pretreatment with SB203580, a p38 MAPK inhibitor also dose-dependently inhibited PRE084-induced MA, whereas TH induction was not affected. In CCI rats, i.t. injection of BD1047 during the induction phase (postoperative days 0 to 5) reduced the CCI-induced increase in p-p38 MAPK. In addition, i.t. SB203580 treatment during the induction phase also suppressed the development of CCI-induced MA, but not TH. Conversely, i.t. SB203580 treatment during the maintenance phase (postoperative days 15 to 20) had no effect on CCI-induced MA or TH. These results demonstrate that the increase in spinal p-p38 MAPK is closely associated with the induction of Sig-1R mediated MA, but not TH. Sigma-1 receptor modulation of p-p38 MAPK also plays an important role in the induction, but not the maintenance, of MA in neuropathic pain.

Original languageEnglish (US)
Pages (from-to)383-391
Number of pages9
JournalExperimental Neurology
StatePublished - Sep 2013

Bibliographical note

Funding Information:
This research was supported by a grant ( 2012K001118 ) from Brain Research Center of the 21st Century Frontier Research Program funded by the Ministry of Education, Science and Technology , the Republic of Korea. This research was also supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MEST) (no. 2012-0005436 ).


  • Mechanical allodynia
  • Neuropathic pain
  • P38 MAPK
  • Sigma-1 receptor


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