Nociceptive sensitization by complement C5a and C3a in mouse.
Activation of the complement system by injury increases inflammation by producing complement fragments C5a and C3a which are able to recruit and activate immune cells. Complement activation may contribute to pain after inflammation and injury. In this study, we examined whether C5a and C3a elicit nociception when injected into mouse hind paws in vivo, and whether C5a and C3a activate and/or sensitize mechanosensitive nociceptors when applied on peripheral terminals in vitro. We also examined the dorsal root ganglia (DRG) for C5a receptor (C5aR) mRNA and effects of C5a and C3a on intracellular Ca(2+) concentration ([Ca(2+)](i)) using Ca(2+) imaging. Heat hyperalgesia was elicited by intraplantar injection of C5a, and mechanical hyperalgesia by C5a and C3a. After exposure to either C5a or C3a, C-nociceptors were sensitized to heat as evidenced by an increased proportion of heat responsive fibers, lowered response threshold to heat and increased action potentials during and after heat stimulation. A-nociceptors were activated by complement. However, no change was observed in mechanical responses of A- and C-nociceptors after C5a and C3a application. The presence of C5aR mRNA was detected in DRG. C5a and C3a application elevated [Ca(2+)](i) and facilitated capsaicin-induced [Ca(2+)](i) responses in DRG neurons. The results suggest a potential role for complement fragments C5a and C3a in nociception by activating and sensitizing cutaneous nociceptors.
Jang
Jun Ho
JH
Department of Anesthesia, University of Iowa Hospitals and Clinics, Iowa City, IA, USA Department of Anesthesia, Veterans Affairs Palo Alto Healthcare System and Stanford University School of Medicine, Stanford, CA, USA Department of Pharmacology, University of Iowa, Iowa City, IA, USA Graduate Program of Neuroscience, University of Iowa, Iowa City, IA, USA.
Clark
David J
DJ
Li
Xiangqi
X
Yorek
Matthew S
MS
Usachev
Yuriy M
YM
Brennan
Timothy J
TJ
D000200:Action Potentials / Q000187:drug effects; D000704:Analysis of Variance; D000818:Animals; D019703:Calcineurin / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002211:Capsaicin / Q000494:pharmacology; D015926:Complement C3a / Q000494:pharmacology*; D015936:Complement C5a / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005106:Exploratory Behavior / Q000187:drug effects; D005727:Ganglia, Spinal / Q000166:cytology; D006801:Humans; D006930:Hyperalgesia / Q000145:classification / Q000503:physiopathology; D007155:Immunologic Factors / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009412:Nerve Fibers / Q000187:drug effects / Q000502:physiology; D009619:Nociceptors / Q000187:drug effects* / Q000502:physiology; D010147:Pain Measurement / Q000379:methods; D017288:Pain Threshold / Q000187:drug effects*; D010812:Physical Stimulation / Q000379:methods; D012333:RNA, Messenger / Q000378:metabolism; D011930:Reaction Time / Q000187:drug effects; D011984:Sensory Receptor Cells / Q000187:drug effects; D012867:Skin / Q000294:innervation
D007155:Immunologic Factors; D012333:RNA, Messenger; D015926:Complement C3a; D015936:Complement C5a; D019703:Calcineurin; D002211:Capsaicin; D002118:Calcium