Journal article
Mechanisms underlying mechanical sensitization induced by complement C5a: the roles of macrophages, TRPV1, and calcitonin gene-related peptide receptors
Pain (Amsterdam), Vol.160(3), pp.702-711
03/2019
DOI: 10.1097/j.pain.0000000000001449
PMCID: PMC6377341
PMID: 30507785
Abstract
The complement system significantly contributes to the development of inflammatory and neuropathic pain, but the underlying mechanisms are poorly understood. Recently, we identified the signaling pathway responsible for thermal hypersensitivity induced by the complement system component C5a. Here, we examine the mechanisms of another important action of C5a, induction of mechanical hypersensitivity. We found that intraplantar injection of C5a produced a dose-dependent mechanical sensitization and that this effect was blocked by chemogenetic ablation of macrophages in both male and female mice. Knockout of TRPV1 or pretreatment with the TRPV1 antagonists, AMG9810 or 5'-iodoresiniferatoxin (5'-IRTX), significantly reduced C5a-induced mechanical sensitization. Notably, local administration of 5'-IRTX 90 minutes after C5a injection resulted in a slow, but complete, reversal of mechanical sensitization, indicating that TRPV1 activity was required for maintaining C5a-induced mechanical hypersensitivity. This slow reversal suggests that neurogenic inflammation and neuropeptide release may be involved. Indeed, pretreatment with a calcitonin gene-related peptide (CGRP) receptor antagonist (but not an antagonist of the neurokinin 1 receptor) prevented C5a-induced mechanical sensitization. Furthermore, intraplantar injection of CGRP produced significant mechanical sensitization in both wild-type and TRPV1 knockout mice. Taken together, these findings suggest that C5a produces mechanical sensitization by initiating macrophage-to-sensory-neuron signaling cascade that involves activation of TRPV1 and CGRP receptor as critical steps in this process.
Details
- Title: Subtitle
- Mechanisms underlying mechanical sensitization induced by complement C5a: the roles of macrophages, TRPV1, and calcitonin gene-related peptide receptors
- Creators
- Charles A Warwick - Department of Pharmacology, Iowa Neuroscience Institute, University of Iowa, Iowa City, IA, United StatesLeonid P Shutov - Department of Pharmacology, Iowa Neuroscience Institute, University of Iowa, Iowa City, IA, United StatesAndrew J Shepherd - Department of Anesthesiology, Washington University Pain Center, Washington University School of Medicine, St. Louis, MO, United StatesDurga P Mohapatra - Department of Anesthesiology, Washington University Pain Center, Washington University School of Medicine, St. Louis, MO, United StatesYuriy M Usachev - Department of Pharmacology, Iowa Neuroscience Institute, University of Iowa, Iowa City, IA, United States
- Resource Type
- Journal article
- Publication Details
- Pain (Amsterdam), Vol.160(3), pp.702-711
- Publisher
- United States
- DOI
- 10.1097/j.pain.0000000000001449
- PMID
- 30507785
- PMCID
- PMC6377341
- ISSN
- 0304-3959
- eISSN
- 1872-6623
- Grant note
- T32 NS073548 / NINDS NIH HHS R01 NS096246 / NINDS NIH HHS P30 DK056341 / NIDDK NIH HHS R01 DK116624 / NIDDK NIH HHS R01 NS087068 / NINDS NIH HHS
- Language
- English
- Date published
- 03/2019
- Academic Unit
- Iowa Neuroscience Institute; Anesthesia; Fraternal Order of Eagles Diabetes Research Center; Neuroscience and Pharmacology
- Record Identifier
- 9984070843602771
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