Spinal CCL2 pronociceptive action is no longer effective in CCR2 receptor antagonist-treated rats.
A better understanding of the mechanisms linked to chemokine pronociceptive effects is essential for the development of new strategies to better prevent and treat chronic pain. Among chemokines, MCP-1/CCL2 involvement in neuropathic pain processing is now established. However, the mechanisms by which MCP-1/CCL2 exerts its pronociceptive effects are still poorly understood. In the present study, we demonstrate that MCP-1/CCL2 can alter pain neurotransmission in healthy rats. Using immunohistochemical studies, we first show that CCL2 is constitutively expressed by primary afferent neurons and their processes in the dorsal horn of the spinal cord. We also observe that CCL2 is co-localized with pain-related peptides (SP and CGRP) and capsaicin receptor (VR1). Accordingly, using in vitro superfusion system of lumbar dorsal root ganglion and spinal cord explants of healthy rats, we show that potassium or capsaicin evoke calcium-dependent release of CCL2. In vivo, we demonstrate that intrathecal administration of CCL2 to healthy rats produces both thermal hyperalgesia and sustained mechanical allodynia (up to four consecutive days). These pronociceptive effects of CCL2 are completely prevented by the selective CCR2 antagonist (INCB3344), indicating that CCL2-induced pain facilitation is elicited via direct spinal activation of CCR2 receptor. Therefore, preventing the activation of CCR2 might provide a fruitful strategy for treating pain.
Dansereau
Marc-André
MA
Department of Physiology and Biophysics, Faculty of Medicine and Health Sciences, University of Sherbrooke, Sherbrooke, Quebec, Canada.
Gosselin
Romain-Daniel
RD
Pohl
Michel
M
Pommier
Blandine
B
Mechighel
Patricia
P
Mauborgne
Annie
A
Rostene
William
W
Kitabgi
Patrick
P
Beaudet
Nicolas
N
Sarret
Philippe
P
Melik-Parsadaniantz
Stéphane
S
D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal; D015740:Calcitonin Gene-Related Peptide / Q000235:genetics / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005727:Ganglia, Spinal / Q000166:cytology; D005786:Gene Expression Regulation / Q000187:drug effects*; D006930:Hyperalgesia / Q000503:physiopathology*; D008297:Male; D009475:Neurons, Afferent / Q000187:drug effects*; D017288:Pain Threshold / Q000187:drug effects*; D011189:Potassium Chloride / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D054390:Receptors, CCR2 / Q000037:antagonists & inhibitors*; D013116:Spinal Cord / Q000166:cytology*; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism; D013373:Substance P / Q000235:genetics / Q000378:metabolism; D050916:TRPV Cation Channels / Q000235:genetics / Q000378:metabolism
C515336:Ccr2 protein, rat; D018932:Chemokine CCL2; C505875:INCB3344; D011759:Pyrrolidines; D054390:Receptors, CCR2; D050916:TRPV Cation Channels; C494484:TRPV1 receptor; D013373:Substance P; D011189:Potassium Chloride; D015740:Calcitonin Gene-Related Peptide; D002118:Calcium