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Sex-Dependent Glial Signaling in Pathological Pain: Distinct Roles of Spinal Microglia and Astrocytes

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Abstract

Increasing evidence suggests that spinal microglia regulate pathological pain in males. In this study, we investigated the effects of several microglial and astroglial modulators on inflammatory and neuropathic pain following intrathecal injection in male and female mice. These modulators were the microglial inhibitors minocycline and ZVEID (a caspase-6 inhibitor) and the astroglial inhibitors L-α-aminoadipate (L-AA, an astroglial toxin) and carbenoxolone (a connexin 43 inhibitor), as well as U0126 (an ERK kinase inhibitor) and D-JNKI-1 (a c-Jun N-terminal kinase inhibitor). We found that spinal administration of minocycline or ZVEID, or Caspase6 deletion, reduced formalin-induced inflammatory and nerve injury-induced neuropathic pain primarily in male mice. In contrast, intrathecal L-AA reduced neuropathic pain but not inflammatory pain in both sexes. Intrathecal U0126 and D-JNKI-1 reduced neuropathic pain in both sexes. Nerve injury caused spinal upregulation of the astroglial markers GFAP and Connexin 43 in both sexes. Collectively, our data confirmed male-dominant microglial signaling but also revealed sex-independent astroglial signaling in the spinal cord in inflammatory and neuropathic pain.

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Acknowledgements

This work was supported by NIH R01 grants DE17794, DE22743, and NS87988 to RRJ. YJQ was supported by NIH T32 2T32GM008600 and a Foundation of Anesthesia Education and Research Fellowship.

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Authors and Affiliations

  1. Department of Anesthesiology, Duke University Medical Center, Durham, NC, 27710, USA

    Gang Chen, Xin Luo, M. Yawar Qadri, Temugin Berta & Ru-Rong Ji

  2. Key Laboratory of Neuroregeneration of Jiangsu and the Ministry of Education, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, 226001, China

    Gang Chen

  3. Pain Research Center, Department of Anesthesiology, University of Cincinnati Medical Center, Cincinnati, OH, 45267, USA

    Temugin Berta

  4. Department of Neurobiology, Duke University Medical Center, Durham, NC, 27710, USA

    Ru-Rong Ji

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  1. Gang Chen
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Correspondence to Gang Chen.

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Chen, G., Luo, X., Qadri, M.Y. et al. Sex-Dependent Glial Signaling in Pathological Pain: Distinct Roles of Spinal Microglia and Astrocytes. Neurosci. Bull. 34, 98–108 (2018). https://doi.org/10.1007/s12264-017-0145-y

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