Mice overexpressing chemokine ligand 2 (CCL2) in astrocytes display enhanced nociceptive responses

• Published in: Neuroscience Vol. 149; no. 3; pp. 706 - 714
• Main Authors: Menetski, J, Mistry, S, Lu, M, Mudgett, J.S, Ransohoff, R.M, DeMartino, J.A, MacIntyre, D.E, Abbadie, C
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 09.11.2007; Elsevier
• Subjects: Animals; Astrocytes - metabolism; Astrocytes - physiology; Biological and medical sciences; chemokine; Chemokine CCL2 - biosynthesis; Chemokine CCL2 - physiology; Chemokines - biosynthesis; Enzyme-Linked Immunosorbent Assay; Formaldehyde; Freund's Adjuvant; Fundamental and applied biological sciences. Psychology; Ganglia, Spinal - metabolism; hot plate; Hot Temperature; inflammation; Inflammation - chemically induced; Inflammation - complications; Inflammation - physiopathology; Male; Mice; Neurology; neuropathy; pain; Pain - physiopathology; Pain Measurement; Peripheral Nerve Injuries; Peripheral Nervous System Diseases - complications; Peripheral Nervous System Diseases - physiopathology; Phenotype; Physical Stimulation; Reaction Time - physiology; Reverse Transcriptase Polymerase Chain Reaction; Schwann Cells - physiology; Somesthesis and somesthetic pathways (proprioception, exteroception, nociception); interoception; electrolocation. Sensory receptors; Spinal Cord - physiology; transgenic; Vertebrates: nervous system and sense organs; chemokine; pain; dorsal root ganglia; CNS; peripheral nervous system; TRPV1; CC chemokine ligand 2; central nervous system; GFAP; analysis of variance; PNS; inflammation; ANOVA; transient receptor potential vanilloid subunit one channel; DRG; hot plate; neuropathy; CCL2; transgenic; complete Freund’s adjuvant; glial fibrillary acidic protein; CCR2; chemokine receptor 2; CFA; Nociception; Neuroglia; Rodentia; Transgenic animal; Gene overexpression; Inflammation; Astrocyte; Chemokine; Vertebrata; Mammalia; Pain; Mouse
• ISSN: 0306-4522; 1873-7544
• DOI: 10.1016/j.neuroscience.2007.08.014

Abstract 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-1β, IL-6, and TNFα) 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.