Σ1 receptors activate astrocytes via p38 MAPK phosphorylation leading to the development of mechanical allodynia in a mouse model of neuropathic pain. (24th November 2014)

• Record Type: Journal Article
• Authors: Moon, J Y; Roh, D H; Yoon, S Y; Choi, S R; Kwon, S G; Choi, H S; Kang, S Y; Han, H J; Beitz, A J; Oh, S B; Lee, J H
• Is Part Of: British journal of pharmacology. Volume 171:Number 24(2014:Dec.)
• Page Start: 5881
• Page End: 5897
• Publication Date: 2014-11-24
• Subjects: Pharmacology -- Periodicals; Chemotherapy -- Periodicals; Drug Therapy -- Periodicals; Pharmacology -- Periodicals; 615.1
• DOI: 10.1111/bph.12893
• Languages: English
• ISSNs: 0007-1188

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="bph12893-sec-0001" sec-type="section"> <title>Background and Purpose</title> <p>Spinal astrocytes have emerged as important mechanistic contributors to the genesis of mechanical allodynia (MA) in neuropathic pain. We recently demonstrated that the spinal sigma non‐opioid intracellular receptor 1 (σ1 receptor) modulates p38 MAPK phosphorylation (p‐p38), which plays a critical role in the induction of MA in neuropathic rats. However, the histological and physiological relationships among σ1, p‐p38 and astrocyte activation is unclear.</p> </sec> <sec id="bph12893-sec-0002" sec-type="section"> <title>Experimental Approach</title> <p>We investigated: (i) the precise location of σ1 receptors and p‐p38 in spinal dorsal horn; (ii) whether the inhibition of σ1 receptors or p38 modulates chronic constriction injury (CCI)‐induced astrocyte activation; and (iii) whether this modulation of astrocyte activity is associated with MA development in CCI mice.</p> </sec> <sec id="bph12893-sec-0003" sec-type="section"> <title>Key Results</title> <p>The expression of σ1 receptors was significantly increased in astrocytes on day 3 following CCI surgery. Sustained intrathecal treatment with the σ1 antagonist, BD‐1047, attenuated CCI‐induced increase in GFAP‐immunoreactive astrocytes, and the treatment combined with fluorocitrate, an astrocyte metabolic inhibitor, synergistically reduced the development of MA, but not thermal hyperalgesia. The number of p‐p38‐ir astrocytes and neurons, but not microglia was significantly increased. Interestingly, intrathecal BD‐1047 attenuated the expression of p‐p38 selectively in astrocytes but not in neurons. Moreover, intrathecal treatment with a p38 inhibitor attenuated the GFAP expression, and this treatment combined with fluorocitrate synergistically blocked the induction of MA.</p> </sec> <sec id="bph12893-sec-0004" sec-type="section"> <title>Conclusions and Implications</title> <p>Spinal σ1 receptors are localized in astrocytes and blockade of σ1 receptors inhibits the pathological activation of astrocytes via modulation of p‐p38, which ultimately prevents the development of MA in neuropathic mice.</p> </sec> </abstract>