Complement activation in the peripheral nervous system following the spinal nerve ligation model of neuropathic pain ☆

Abstract

Neuroinflammatory and neuroimmune mechanisms, as exemplified by infiltrating immune cells and activation of resident endothelial/glial cells, respectively, are known to be involved in the establishment and maintenance of chronic pain. An immune system pathway that may be involved in the activation of both immune and glial cells is complement. The complement pathway is made up of a large number of distinct plasma proteins which react with one another to opsonize pathogens and induce a series of inflammatory responses to help fight infection. Cleaved products and complexes produced by complement activation are responsible for a range of effects including mediation of immune infiltration, activation of phagocytes, opsonization/lysis of pathogens and injured cells, and production of vasoactive amines such as histamine and serotonin. Gene-expression microarray-analysis performed on the rat spinal nerve ligation (SNL) model of neuropathic pain revealed that multiple complement components including the C1 inhibitor, C1q alpha, beta, and gamma, C1r, C1s, C2, C3, C4, C7, and factors B, D, H, and P, were up-regulated while DAF was down-regulated. Regulation of C3 and DAF was confirmed by real-time RT-PCR and in situ hybridization. To test the hypothesis that complement plays a role in neuropathic pain, SNL rats were treated with cobra venom factor (CVF) to deplete plasma of complement component C3. Pain behavior was significantly attenuated in SNL rats treated with CVF as was complement activity at the ipsilateral dorsal root ganglia. Our results suggest the complement pathway might be a novel target for the development of neuropathic pain therapeutics.

Targeting the minor pocket of C5aR for the rational design of an oral allosteric inhibitor for inflammatory and neuropathic pain relief

“…Considering the aforementioned evidence of a role of C5a in the CNS, the efficacy of DF2593A in the SNI model may arise in part from its permeability to the blood-brain barrier. However, activation of the complement system in the periphery, at the level of nerve injury and dorsal root ganglia, could also contribute to the genesis of neuropathic pain (32,34). In the periphery, DF2593A could disrupt the activation and the recruitment of leukocytes, thus attenuating the direct sensitization of the primary nociceptive neurons expressing C5aR (35).…”

ELK1 Transcription Factor Linked to Dysregulated Striatal Mu Opioid Receptor Signaling Network and OPRM1 Polymorphism in Human Heroin Abusers

“…Total RNA isolation, assessment of RNA integrity, and microarray hybridization were performed as previously described. (36) Expression data were collected using HG-U133A Affymetrix Chips (Affymetrix, Santa Clara, CA). Raw data were normalized using the Robust Multichip Average (RMA)(37) from the Affymetrix Expression Console.…”

Bilateral Changes of Cannabinoid Receptor Type 2 Protein and mRNA in the Dorsal Root Ganglia of a Rat Neuropathic Pain Model

“…Several candidate molecules have been suggested as signaling from the damaged nerve. For example, multiple components of complement activation are regulated in DRG following nerve injury (Levin et al 2008), but further experiments are needed to examine their potential involvement in signaling and changes to CB2R levels in heteronymous DRG.…”