The complement 3a receptor (C3aR1) participates in microglial signaling under pathological conditions and was recently shown to be activated by the neuropeptide TLQP‐21. We previously demonstrated that TLQP‐21 elicits hyperalgesia and contributes to nerve injury‐induced hypersensitivity through an unknown mechanism in the spinal cord. Here we determined that this mechanism requires C3aR1 and that microglia are the cellular target for TLQP‐21. We propose a novel neuroimmune signaling pathway involving TLQP‐21‐induced activation of microglial C3aR1 that then contributes to spinal neuroplasticity and neuropathic pain. This unique dual‐ligand activation of C3aR1 by a neuropeptide (TLQP‐21) and an immune mediator (C3a) represents a potential broad‐spectrum mechanism throughout the CNS for integration of neuroimmune crosstalk at the molecular level.

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Published in GLIA, v. 65, issue 12, p. 1976-1989.

© 2017 Wiley Periodicals, Inc.

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This is the peer reviewed version of the following article: Doolen, S., Cook, J., Riedl, M., Kitto, K., Kohsaka, S., Honda, C. H., ... Vulchanova, L. (2017). Complement 3a receptor in dorsal horn microglia mediates pronociceptive neuropeptide signaling. GLIA, 65(12), 1976-1989, which has been published in final form at https://doi.org/10.1002/glia.23208. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions.

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This work was supported by R01 NS088518, K01DA031961 (SD), R01DA37621 (BKT), T32DA007234 (JC), T32GM008471 (JC), F31 NS095421 (JC).