The Role of the Peripheral Chemokine, CCL3, in Hyperalgesia following Peripheral Nerve Injury in the Rat

신경손상에 의해 유발된 과민통반응에서 말초 케모카인 CCL3의 역할

  • Leem, Joong Woo (Department of Physiology, Yonsei University Medical College) ;
  • Lee, Hyun Joo (Department of Physiology, Yonsei University Medical College) ;
  • Nam, Taick Sang (Department of Physiology, Yonsei University Medical College) ;
  • Yoon, Duck Mi (Department of Anesthesiology and Pain Medicine and Anesthesia & Pain Research Institute, Yonsei University Medical College)
  • 임중우 (연세대학교 의과대학 생리학교실) ;
  • 이현주 (연세대학교 의과대학 생리학교실) ;
  • 남택상 (연세대학교 의과대학 생리학교실) ;
  • 윤덕미 (연세대학교 의과대학 마취통증의학교실 및 마취통증의학연구소)
  • Received : 2008.10.28
  • Accepted : 2008.11.25
  • Published : 2008.12.30


Background: Upregulation of one type of the pro-inflammatory chemokine (CCL2) and its receptor (CCR2) following peripheral nerve injury contributes to the induction of neuropathic pain. Here, we examined whether another type of chemokine (CCL3) is involved in neuropathic pain. Methods: We measured changes in mechanical and thermal sensitivity in the hind paws of naïve rats or rats with an L5 spinal nerve ligation (SNL) after intra-plantar injection of CCL3 or met-RANTES, an antagonist of the CCL3 receptor, CCR1. We also measured CCL3 levels in the sciatic nerve and the hind paw skin as well as CCR1 expression in dorsal root ganglion (DRG) cells from the lumbar spinal segments. Results: Intra-plantar injection of CCL3 into the hind paw of naive rats mimicked L5 SNL-produced hyperalgesia. Intra-plantar injection of met-RANTES into the hind paw of rats with L5 SNL attenuated hyperalgesia. L5 SNL increased CCL3 levels in the sciatic nerve and the hind paw skin on the affected side. The number of CCR1-positive DRG cells in the lumbar segments was not changed following L5 SNL. Conclusions: Partial peripheral nerve injury increases local CCL3 levels along the degenerating axons during Wallerian degeneration. This CCL3 binds to its receptor, CCR1, located on adjacent uninjured afferents, presumably nociceptors, to induce hyperalgesia in the neuropathic pain state.



Supported by : 연세대학교


  1. Woolf CJ, Mannion RJ: Neuropathic pain: aetiology, symptoms, mechanisms, and management. Lancet 1999; 353: 1959-64
  2. Schroeter M, Jander S: T-cell cytokines in injury-induced neural damage and repair. Neuromolecular Med 2005; 7: 183-95
  3. Scholz J, Woolf CJ: Can we conquer pain? Nat Neurosci 2002; 5(Suppl): 1062-7
  4. Marchand F, Perretti M, McMahon SB: Role of the immune system in chronic pain. Nat Rev Neurosci 2005; 6: 521-32
  5. Rossi D, Zlotnik A: The biology of chemokines and their receptors. Annu Rev Immunol 2000; 18: 217-42
  6. Tran PB, Miller RJ: Chemokine receptors: signposts to brain development and disease. Nat Rev Neurosci 2003; 4: 444-55
  7. White FA, Bhangoo SK, Miller RJ: Chemokines: integrators of pain and inflammation. Nat Rev Drug Discov 2005; 4: 834-44
  8. Taskinen HS, Roytta M: Increased expression of chemokines (MCP-1, MIP-1alpha, RANTES) after peripheral nerve transection. J Peripher Nerv Syst 2000; 5: 75-81
  9. Tanaka T, Minami M, Nakagawa T, Satoh M: Enhanced production of monocyte chemoattractant protein-1 in the dorsal root ganglia in a rat model of neuropathic pain: possible involvement in the development of neuropathic pain. Neurosci Res 2004; 48: 463-9
  10. Carollo M, Hogaboam CM, Kunkel SL, Delaney S, Christie MI, Perretti M: Analysis of the temporal expression of chemokines and chemokine receptors during experimental granulomatous inflammation: role and expression of MIP-1alpha and MCP-1. Br J Pharmacol 2001; 134: 1166-79
  11. Abbadie C: Chemokines, chemokine receptors and pain. Trends Immunol 2005; 26: 529-34
  12. Abbadie C, Lindia JA, Cumiskey AM, Peterson LB, Mudgett JS, Bayne EK, et al: Impaired neuropathic pain responses in mice lacking the chemokine receptor CCR2. Proc Natl Acad Sci U S A 2003; 100: 7947-52
  13. Shahrara S, Amin MA, Woods JM, Haines GK, Koch AE: Chemokine receptor expression and in vivo signaling pathways in the joints of rats with adjuvant-induced arthritis. Arthritis Rheum 2003; 48: 3568-83
  14. Shahrara S, Proudfoot AE, Woods JM, Ruth JH, Amin MA, Park CC, et al: Amelioration of rat adjuvant-induced arthritis by Met-RANTES. Arthritis Rheum 2005; 52: 1907-19
  15. Bhatia M, Proudfoot AE, Wells TN, Christmas S, Neoptolemos JP, Slavin J: Treatment with Met-RANTES reduces lung injury in caerulein-induced pancreatitis. Br J Surg 2003; 90: 698-704
  16. Kim SH, Chung JM: An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat. Pain 1992; 50: 355-63
  17. Jang JH, Nam TS, Yoon DM, Leem JW, Paik GS: Role of peripheral glutamate receptors to mechanical hyperalgesia following nerve injury or antidromic stimulation of L5 spinal nerve in rats with the previous L5 dorsal rhizotomy. Korean J Pain 2006; 19: 33-44
  18. Chaplan SR, Bach FW, Pogrel JW, Chung JM, Yaksh TL: Quantitative assessment of tactile allodynia in the rat paw. J Neurosci Methods 1994; 53: 55-63
  19. Harper AA, Lawson SN: Conduction velocity is related to morphological cell type in rat dorsal root ganglion neurons. J Physiol 1985; 359: 31-46
  20. Barnes DA, Tse J, Kaufhold M, Owen M, Hesselgesser J, Strieter R, et al: Polyclonal antibody directed against human RANTES ameliorates disease in the Lewis rat adjuvantinduced arthritis model. J Clin Invest 1998; 101: 2910-9
  21. Perrin FE, Lacroix S, Aviles-Trigueros M, David S: Involvement of monocyte chemoattractant protein-1, macrophage inflammatory protein-1alpha and interleukin1beta in Wallerian degeneration. Brain 2005; 128: 854-66
  22. Zhang N, Inan S, Cowan A, Sun R, Wang JM, Rogers TJ, et al: A proinflammatory chemokine, CCL3, sensitizes the heat- and capsaicin-gated ion channel TRPV1. Proc Natl Acad Sci U S A 2005; 102: 4536-41
  23. George A, Kleinschnitz C, Zelenka M, Brinkhoff J, Stoll G, Sommer C: Wallerian degeneration after crush or chronic constriction injury of rodent sciatic nerve is associated with a depletion of endoneurial interleukin-10 protein. Exp Neurol 2004; 188: 187-91
  24. Mahad DJ, Trebst C, Kivisakk P, Staugaitis SM, Tucky B, Wei T, et al: Expression of chemokine receptors CCR1 and CCR5 reflects differential activation of mononuclear phagocytes in pattern II and pattern III multiple sclerosis lesions. J Neuropathol Exp Neurol 2004; 63: 262-73
  25. Haas CS, Martinez RJ, Attia N, Haines GK 3rd, Campbell PL, Koch AE: Chemokine receptor expression in rat adjuvant-induced arthritis. Arthritis Rheum 2005; 52: 3718-30
  26. Meyer-Siegler K, Fattor RA, Hudson PB: Expression of macrophage migration inhibitory factor in the human prostate. Diagn Mol Pathol 1998; 7: 44-50