# The Role of the Complement System in Spinal Mechanisms of Chronic Pain

> **NIH NIH R01** · UNIVERSITY OF IOWA · 2021 · $329,852

## Abstract

PROJECT SUMMARY / ABSTRACT
Persistent pain affects 100 million Americans and 15 million Ukrainians. The immune system critically
contributes to pathogenesis of inflammatory and neuropathic pain, and precise understanding of mechanisms
through which particular immune mediators contribute to sensitization of nociceptive neuronal pathways will be
essential for developing more efficacious treatment strategies. The complement system is a principal
component of innate immunity that contributes to host defenses via diverse mechanisms. In spite of growing
evidence implicating the complement system in various chronic pain states, the underlying mechanisms are
not well understood. Our main objectives for this collaborative proposal between the US and Ukrainian groups
are to elucidate complement-dependent spinal mechanisms that contribute to the development of neuropathic
pain, and at a broader level, to promote building and strengthening sustainable research capacity in Ukraine.
Mechanical hypersensitivity and spontaneous pain are common features of neuropathic pain. The main
nociceptive output pathway from the spinal cord to the brain underlying this abnormal pain processing is lamina
I projection neurons (PNs) of dorsal horn (DH). Our patch-clamp recordings from these neurons using an
innovative intact spinal cord preparation demonstrate abnormal regulation of spinal cord output following
spared nerve injury (SNI), a common model of neuropathic pain that well reproduces many features of clinical
neuropathic pain. Recent studies suggest that neuropathic pain is associated with a robust upregulation of
complement effectors in the spinal cord, which ultimately leads to production of a highly active complement
product, C5a. Intrathecal administration of C5a produces allodynia, whereas C5 knockout (KO) and C5a
receptor (C5aR1) antagonists produce analgesic effects in animal models of neuropathic pain. Our preliminary
data show that C5aR1 KO prevents mechanical hypersensitivity following SNI. C5aR1 in the DH is found
primarily on microglia that is known to be activated in the DH after SNI. Moreover C5aR1 expression is
increased after SNI. We will use a multidisciplinary approach including patch-clamp recordings, optogenetic
stimulation and multi-photon Ca2+ imaging in innovative intact spinal cord preparation combined with behavioral
pharmacology to test our central hypothesis that C5a/C5aR1 signaling plays important roles in neuropathic
pain processing by impacting central sensitization via microglia-dependent signaling that enhances the output
of lamina I PNs of the DH to the supraspinal structures. This proposal will provide mechanistic insight into the
function of the complement system in the CNS pain processing, and may lead to the development of new
analgesic drugs that target complement system. In its broader impact, this project will promote establishment
of Center for Excellence in brain disorder research in Ukraine, and help attracting young Ukrainia...

## Key facts

- **NIH application ID:** 10165843
- **Project number:** 5R01NS113189-03
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** Yuriy M Usachev
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $329,852
- **Award type:** 5
- **Project period:** 2019-06-15 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10165843

## Citation

> US National Institutes of Health, RePORTER application 10165843, The Role of the Complement System in Spinal Mechanisms of Chronic Pain (5R01NS113189-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10165843. Licensed CC0.

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