Complement induction in spinal cord microglia results in anaphylatoxin C5a-mediated pain hypersensitivity.
Microarray expression profiles reveal substantial changes in gene expression in the ipsilateral dorsal horn of the spinal cord in response to three peripheral nerve injury models of neuropathic pain. However, only 54 of the 612 regulated genes are commonly expressed across all the neuropathic pain models. Many of the commonly regulated transcripts are immune related and include the complement components C1q, C3, and C4, which we find are expressed only by microglia. C1q and C4 are, moreover, the most strongly regulated of all 612 regulated genes. In addition, we find that the terminal complement component C5 and the C5a receptor (C5aR) are upregulated in spinal microglia after peripheral nerve injury. Mice null for C5 had reduced neuropathic pain sensitivity, excluding C3a as a pain effector. C6-deficient rats, which cannot form the membrane attack complex, have a normal neuropathic pain phenotype. However, C5a applied intrathecally produces a dose-dependent, slow-onset cold pain in naive animals. Furthermore, a C5aR peptide antagonist reduces cold allodynia in neuropathic pain models. We conclude that induction of the complement cascade in spinal cord microglia after peripheral nerve injury contributes to neuropathic pain through the release and action of the C5a anaphylatoxin peptide.
Neural Plasticity Research Group, Department of Anesthesia and Critical Care, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129, USA.
Robert S
RS
Griffin
Michael
M
Costigan
Gary J
GJ
Brenner
Chi Him Eddie
CH
Ma
Joachim
J
Scholz
Andrew
A
Moss
Andrew J
AJ
Allchorne
Gregory L
GL
Stahl
Clifford J
CJ
Woolf
D000706:Anaphylatoxins / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D000818:Animals; D002478:Cells, Cultured; D015936:Complement C5a / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D005786:Gene Expression Regulation / Q000502:physiology; D006930:Hyperalgesia / Q000235:genetics / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000378:metabolism*; D010146:Pain / Q000235:genetics / Q000378:metabolism*; D010147:Pain Measurement / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D044087:Receptor, Anaphylatoxin C5a; D011951:Receptors, Complement / Q000096:biosynthesis / Q000235:genetics; D013116:Spinal Cord / Q000378:metabolism*
D000706:Anaphylatoxins; C488033:C5AR1 protein, human; D008565:Membrane Proteins; D044087:Receptor, Anaphylatoxin C5a; D011951:Receptors, Complement; D015936:Complement C5a