Mice overexpressing chemokine ligand 2 (CCL2) in astrocytes display enhanced nociceptive responses.
Recent findings demonstrate that chemokines, and more specifically CC chemokine ligand 2 (CCL2 or monocyte chemoattractant protein-1), play a major role in pain processing. In the present study, we assess nociceptive responses of mice that overexpressed CCL2 under control of glial fibrillary acidic protein promoter (CCL2 tg). In models of acute nociception CCL2 tg mice demonstrated significantly enhanced nociceptive behavior relative to wild-type controls in responses to both thermal (hot plate) and chemical (formalin test) stimulus modalities. There were no differences in mechanical allodynia in the partial sciatic nerve ligation model, in terms of either magnitude or duration of the allodynic response; however, both groups responded to the maximal extent measurable. In a model of inflammatory pain, elicited by intraplantar administration of complete Freund's adjuvant (CFA), CCL2 tg mice displayed both greater edema and thermal hyperalgesia compared with control mice. In control mice, edema and hyperalgesia returned to baseline values 5-7 days post CFA. However, in CCL2 tg mice, thermal hyperalgesia was significantly different from baseline up to 3 weeks post CFA. Parallel to these enhanced behavioral responses CCL2 serum levels were significantly greater in CCL2 overexpressing mice and remained elevated 7 days post CFA. Consequently, proinflammatory cytokine mRNA expression (IL-1beta, IL-6, and TNFalpha) levels were greater in skin, dorsal root ganglia (DRG), and spinal cord, whereas the anti-inflammatory cytokine (IL-10) level was lower in skin and DRG in CCL2 overexpressing mice than in control mice. Taken together with data from CCR2-deficient mice, these present data confirm a key role of CCL2/CCR2 axis in pain pathways and suggest that inhibiting this axis may result in novel pain therapies.
Menetski
J
J
Department of Immunology and Rheumatology, Merck Research Laboratories, P.O. Box 2000, Rahway, NJ 07065, USA.
Mistry
S
S
Lu
M
M
Mudgett
J S
JS
Ransohoff
R M
RM
Demartino
J A
JA
Macintyre
D E
DE
Abbadie
C
C
D000818:Animals; D001253:Astrocytes / Q000378:metabolism / Q000502:physiology*; D018932:Chemokine CCL2 / Q000096:biosynthesis* / Q000502:physiology*; D018925:Chemokines / Q000096:biosynthesis; D004797:Enzyme-Linked Immunosorbent Assay; D005557:Formaldehyde; D005620:Freund's Adjuvant; D005727:Ganglia, Spinal / Q000378:metabolism; D006358:Hot Temperature; D007249:Inflammation / Q000139:chemically induced / Q000150:complications / Q000503:physiopathology; D008297:Male; D051379:Mice; D010146:Pain / Q000503:physiopathology*; D010147:Pain Measurement; D059348:Peripheral Nerve Injuries; D010523:Peripheral Nervous System Diseases / Q000150:complications / Q000503:physiopathology; D010641:Phenotype; D010812:Physical Stimulation; D011930:Reaction Time / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012583:Schwann Cells / Q000502:physiology; D013116:Spinal Cord / Q000502:physiology
D018932:Chemokine CCL2; D018925:Chemokines; D005557:Formaldehyde; D005620:Freund's Adjuvant