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Function and Expression of Complement C5aR1 Receptor in the Spinal Cord in Neuropathic Pain
Abstract   Peer reviewed

Function and Expression of Complement C5aR1 Receptor in the Spinal Cord in Neuropathic Pain

Alex Keyes, Kavita Solanki, Ritu Som, Yaroslav Andrianov, Leonid Shutov, Charles Warwick, Pavel Belan, Nana Voitenko, Trent Woodruff and Yuriy Usachev
The journal of pain, Vol.41, 105737
03/2026
DOI: 10.1016/j.jpain.2025.105737

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Abstract

Chronic neuropathic pain affects approximately 10% of the population and only a minority of patients experience satisfactory relief of their pain with currently available pharmaceutics. Recent meta-analyses have identified pain-regulated genes, most notably complement system activation. Among the complement products, C5a seems to be especially important in the development and maintenance of neuropathic pain. Indeed, C5a receptor (C5aR1), a G-protein coupled receptor that mediates a majority of the effects of C5a, is expressed primarily on microglia in the CNS and is upregulated along with C5a in the dorsal horn of the spinal cord after peripheral nerve injury. Here, we address the role of C5a/C5aR1 signaling in mechanical pain following spared nerve injury (SNI) via behavioral pharmacology. We evaluated molecular changes occurring after SNI by RNASeq. We additionally examine changes in microglial signaling in the dorsal horn by performing 2-photon Ca2+ imaging in microglia in an ex vivo intact spinal cord preparation. Pharmacological or genetic inhibition of C5a/C5aR1 signaling decreased mechanical allodynia. C5a induced Ca2+ signaling in microglia in a dose-dependent manner and was blocked by co-application of a C5aR1 specific antagonist, PMX205. Overall, our findings suggest that C5a/C5aR1 signaling in the spinal dorsal horn plays a key role in modulation of pain hypersensitivity following SNI. Molecular and cellular mechanisms that link C5a/C5aR1 signaling with neuropathic pain are under investigation. Funding: National Institutes of Health (R01 NS131189).

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