期刊
BRITISH JOURNAL OF PHARMACOLOGY
卷 171, 期 24, 页码 5881-5897出版社
WILEY
DOI: 10.1111/bph.12893
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资金
- National Research Foundation (NRF) - Korean Government (MSIP), Korea [2014R1A2A2A01007695, 2012R1A3A2048834]
- National Research Foundation of Korea [2014R1A2A2A01007695, 2012R1A3A2048834] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
Background and PurposeSpinal 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 (sigma 1 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 sigma 1, p-p38 and astrocyte activation is unclear. Experimental ApproachWe investigated: (i) the precise location of sigma 1 receptors and p-p38 in spinal dorsal horn; (ii) whether the inhibition of sigma 1 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. Key ResultsThe expression of sigma 1 receptors was significantly increased in astrocytes on day 3 following CCI surgery. Sustained intrathecal treatment with the sigma 1 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. Conclusions and ImplicationsSpinal sigma 1 receptors are localized in astrocytes and blockade of sigma 1 receptors inhibits the pathological activation of astrocytes via modulation of p-p38, which ultimately prevents the development of MA in neuropathic mice.
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