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PNAS 100 (13): 7947-7952

Copyright © 2003 by the National Academy of Sciences.

Impaired neuropathic pain responses in mice lacking the chemokine receptor CCR2

Catherine Abbadie*,{dagger}, Jill A. Lindia*, Anne Marie Cumiskey*, Larry B. Peterson*, John S. Mudgett{ddagger}, Ellen K. Bayne{ddagger}, Julie A. DeMartino{ddagger}, D. Euan MacIntyre*, and Michael J. Forrest*

*Departments of Pharmacology and {ddagger}Immunology and Rheumatology, Merck Research Laboratories, P.O. Box 2000, Rahway, NJ 07065

Figure 3
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Fig. 3. CCR2 expression after chronic injury in the skin (A), sciatic nerve (B and C), DRG (D and E), and dorsal horn of the spinal cord (F–I). Numerous monocytes/macrophages express CCR2 in the skin dermis (d) and around blood vessels (arrows in A) 2 days after CFA injection into the mouse hindpaw. Fewer CCR2 monocytes/macrophages are found in the sciatic nerve (not shown) and the DRG (D) after CFA. Conversely, abundant CCR2 cells are found both in the perineurium (P) (B) and surrounding axons (as seen with CGRP-LI; C) in the sciatic nerve and the DRG (E). Nerve injury induced the activation of both astrocytes and microglia in the spinal cord. However, CCR2-expressing cells do not colocalize with astrocyte marker (glial fibrillary acidic protein; F) but colocalize with microglia marker (OX-42; arrowheads in G–I) in the dorsal horn of the spinal cord. Not all microglia express CCR2 (green arrow in I). (Bar in G = 100 µmin A and B;25 µmin D and E; and 10 µm in C and F–I.)


Figure 1
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Fig. 1. Nociceptive responses to thermal or chemical stimulations. (A) Licking or jumping latency in the hot-plate assay; no differences between the two groups of mice. (B) Duration of licking and lifting in response to intraplantar formalin injection is significantly reduced in the homozygous mutant as compared with wild-type mice. (C) Area under the curve in B showing slight reduction in phase 1 (0–10 min) but a significant decrease in phase 2 (15–50 min) in mutant as compared with wild-type mice. (D) Mechanical allodynia after intraplantar MCP-1: maximal allodynia is detected 90 min after the injection. *, P < 0.05.


Figure 2
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Fig. 2. Nociceptive responses after two types of chronic pain: inflammation (A and B) and nerve injury (C). (A) Withdrawal threshold to mechanical stimulation (von Frey): mutant mice show a nonsignificant reduction in mechanical allodynia after CFA. (B) Paw withdrawal latencies to noxious thermal stimuli: no differences between the two groups. (C) After nerve injury, mutant mice did not display mechanical allodynia. *, P < 0.05.


Figure 4
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Fig. 4. Activated glial cells in the ipsilateral dorsal horn of the spinal cord 1 wk after partial sciatic nerve ligation. (A and B) The number of glial fibrillary acidic protein-positive cells was decreased (see arrows) in the superficial laminae in the CCR2-/- (B) as compared with the CCR2+/+ mice (A). Similarly, the number of microglia expressing phospho p38 mitogen-activated protein kinase (pp38, C and D) is lower in the CCR2 knockout mice (D) than in wild type (C). (C and D Insets) Higher magnification of laminae I and II. (Bar in D = 200 µm.)


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