Skip to main content

Advertisement

SpringerLink
Log in

Increased function of the TRPV1 channel in small sensory neurons after local inflammation or in vitro exposure to the pro-inflammatory cytokine GRO/KC

  • Original Article
  • Published:
Neuroscience Bulletin Aims and scope Submit manuscript

Abstract

Objective

Inflammation at the level of the sensory dorsal root ganglia (DRGs) leads to robust mechanical pain behavior and the local inflammation has direct excitatory effects on sensory neurons including small, primarily nociceptive, neurons. These neurons express the transient receptor potential vanilloid-1 (TRPV1) channel, which integrates multiple signals of pain and inflammation. The aim of this study was to characterize the regulation of the TRPV1 channel by local DRG inflammation and by growth-related oncogene (GRO/KC, systemic name: CXCL1), a cytokine known to be upregulated in inflamed DRGs.

Methods

Activation of the TRPV1 receptor with capsaicin was studied with patch clamp methods in acutely isolated small-diameter rat sensory neurons in primary culture. In vivo, behavioral effects of TRPV1 and GRO/KC were examined by paw injections.

Results

Neurons isolated from lumbar DRGs 3 days after local inflammation showed enhanced TRPV1 function: tachyphylaxis (the decline in response to repeated applications of capsaicin) was significantly reduced. A similar effect on tachyphylaxis was observed in neurons pre-treated for 4 h in vitro with GRO/KC. This effect was blocked by H-89, a protein kinase A inhibitor. Consistent with the in vitro results, in vivo behavioral responses to paw injection of capsaicin were enhanced and prolonged by pre-injecting the paw with GRO/KC 4 h before the capsaicin injection. GRO/KC paw injections alone did not elicit pain behaviors.

Conclusion

Function of the TRPV1 channel is enhanced by DRG inflammation and these effects are preserved in vitro during short-term culture. The effects (decreased tachyphylaxis) are mimicked by incubation with GRO/KC, which has previously been found to be strongly upregulated in this and other pain models.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Xie WR, Deng H, Li H, Bowen TL, Strong JA, Zhang JM. Robust increase of cutaneous sensitivity, cytokine production and sympathetic sprouting in rats with localized inflammatory irritation of the spinal ganglia. Neuroscience 2006: 142: 809–822.

    Article  PubMed  CAS  Google Scholar 

  2. Xie W, Strong JA, Kim D, Shahrestani S, Zhang JM. Bursting activity in myelinated sensory neurons plays a key role in pain behavior induced by localized inflammation of the rat sensory ganglion. Neuroscience 2012, doi: 10.1016/j.neuroscience.2012.01.007.

  3. Li H, Xie W, Strong JA, Zhang JM. Systemic antiinflammatory corticosteroid reduces mechanical pain behavior, sympathetic sprouting, and elevation of proinflammatory cytokines in a rat model of neuropathic pain. Anesthesiology 2007: 107: 469–477.

    Article  PubMed  CAS  Google Scholar 

  4. Wang JG, Strong JA, Xie W, Zhang JM. Local inflammation in rat dorsal root ganglion alters excitability and ion currents in smalldiameter sensory neurons. Anesthesiology 2007: 107: 322–332.

    Article  PubMed  Google Scholar 

  5. Wang JG, Strong JA, Xie W, Yang RH, Coyle DE, Wick DM, et al. The chemokine CXCL1/growth related oncogene increases sodium currents and neuronal excitability in small diameter sensory neurons. Mol Pain 2008, 4: 38.

    Article  PubMed  Google Scholar 

  6. Yang RH, Strong JA, Zhang JM. NF-kappaB mediated enhancement of potassium currents by the chemokine CXCL1/growth related oncogene in small diameter rat sensory neurons. Mol Pain 2009, 5: 26.

    Article  PubMed  Google Scholar 

  7. Planells-Cases R, Valente P, Ferrer-Montiel A, Qin F, Szallasi A. Complex regulation of TRPV1 and related thermo-TRPs: implications for therapeutic intervention. Adv Exp Med Biol 2011, 704: 491–515.

    Article  PubMed  Google Scholar 

  8. Zhang H, Cang CL, Kawasaki Y, Liang LL, Zhang YQ, Ji RR, et al. Neurokinin-1 receptor enhances TRPV1 activity in primary sensory neurons via PKCepsilon: a novel pathway for heat hyperalgesia. J Neurosci 2007, 27: 12067–12077.

    Article  PubMed  CAS  Google Scholar 

  9. Chung MK, Jung SJ, Oh SB. Role of TRP channels in pain sensation. Adv Exp Med Biol 2011, 704: 615–636.

    Article  PubMed  Google Scholar 

  10. Koplas PA, Rosenberg RL, Oxford GS. The role of calcium in the desensitization of capsaicin responses in rat dorsal root ganglion neurons. J Neurosci 1997, 17: 3525–3537.

    PubMed  CAS  Google Scholar 

  11. Docherty RJ, Yeats JC, Bevan S, Boddeke HW. Inhibition of calcineurin inhibits the desensitization of capsaicin-evoked currents in cultured dorsal root ganglion neurones from adult rats. Pflugers Arch 1996, 431: 828–837.

    PubMed  CAS  Google Scholar 

  12. 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.

    Article  PubMed  CAS  Google Scholar 

  13. Hargreaves K, Dubner R, Brown F, Flores C, Joris J. A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia. Pain 1988, 32: 77–88.

    Article  PubMed  CAS  Google Scholar 

  14. Rozen S, Skaletsky H. Primer3 on the www for general users and for biologist programmers. Methods Mol Biol 2000, 132: 365–386.

    PubMed  CAS  Google Scholar 

  15. Ruijter JM, Ramakers C, Hoogaars WM, Karlen Y, Bakker O, van den Hoff MJ, et al. Amplification efficiency: linking baseline and bias in the analysis of quantitative PCR data. Nucleic Acids Res 2009, 37(6): e45

    Article  PubMed  CAS  Google Scholar 

  16. Shu X, Mendell LM. Acute sensitization by NGF of the response of small-diameter sensory neurons to capsaicin. J Neurophysiol 2001, 86: 2931–2938.

    PubMed  CAS  Google Scholar 

  17. Jerman JC, Brough SJ, Prinjha R, Harries MH, Davis JB, Smart D. Characterization using FLIPR of rat vanilloid receptor (rVR1) pharmacology. Br J Pharmacol 2000, 130: 916–922.

    Article  PubMed  CAS  Google Scholar 

  18. Hong S, Wiley JW. Early painful diabetic neuropathy is associated with differential changes in the expression and function of vanilloid receptor 1. J Biol Chem 2005: 280: 618–627.

    PubMed  CAS  Google Scholar 

  19. Sculptoreanu A, de Groat WC, Buffington CA, Birder LA. Protein kinase C contributes to abnormal capsaicin responses in DRG neurons from cats with feline interstitial cystitis. Neurosci Lett 2005, 381: 42–46.

    Article  PubMed  CAS  Google Scholar 

  20. Zhang N, Inan S, Cowan A, Sun R, Wang JM, Rogers TJ, et al. A proinflammatory chemokine, CCL3, sensitizes the heat- and capsaicingated ion channel TRPV1. Proc Natl Acad Sci U S A 2005, 102: 4536–4541.

    Article  PubMed  CAS  Google Scholar 

  21. Shu X, Mendell LM. Nerve growth factor acutely sensitizes the response of adult rat sensory neurons to capsaicin. Neurosci Lett 1999, 274: 159–162.

    Article  PubMed  CAS  Google Scholar 

  22. Huang J, Zhang X, McNaughton PA. Inflammatory pain: the cellular basis of heat hyperalgesia. Curr Neuropharmacol 2006, 4: 197–206.

    Article  PubMed  CAS  Google Scholar 

  23. Malin SA, Molliver DC, Koerber HR, Cornuet P, Frye R, Albers KM, et al. Glial cell line-derived neurotrophic factor family members sensitize nociceptors in vitro and produce thermal hyperalgesia in vivo. J Neurosci 2006, 26: 8588–8599.

    Article  PubMed  CAS  Google Scholar 

  24. Bhave G, Zhu W, Wang H, Brasier DJ, Oxford GS, Gereau RW4th. cAMP-dependent protein kinase regulates desensitization of the capsaicin receptor (VR1) by direct phosphorylation. Neuron 2002, 35: 721–731.

    Article  PubMed  CAS  Google Scholar 

  25. Zlotnik A, Yoshie O. Chemokines: a new classification system and their role in immunity. Immunity 2000, 12: 121–127.

    Article  PubMed  CAS  Google Scholar 

  26. Neel NF, Barzik M, Raman D, Sobolik-Delmaire T, Sai J, Ham AJ, et al. VASP is a CXCR2-interacting protein that regulates CXCR2-mediated polarization and chemotaxis. J Cell Sci 2009, 122: 1882–1894.

    Article  PubMed  CAS  Google Scholar 

  27. Hu HJ, Bhave G, Gereau RWt. Prostaglandin and protein kinase A-dependent modulation of vanilloid receptor function by metabotropic glutamate receptor 5: potential mechanism for thermal hyperalgesia. J Neurosci 2002, 22: 7444–7452.

    PubMed  CAS  Google Scholar 

  28. Patwardhan AM, Scotland PE, Akopian AN, Hargreaves KM. Activation of TRPV1 in the spinal cord by oxidized linoleic acid metabolites contributes to inflammatory hyperalgesia. Proc Natl Acad Sci U S A 2009, 106: 18820–18824.

    Article  PubMed  CAS  Google Scholar 

  29. Kanai Y, Hara T, Imai A, Sakakibara A. Differential involvement of TRPV1 receptors at the central and peripheral nerves in CFAinduced mechanical and thermal hyperalgesia. J Pharm Pharmacol 2007, 59: 733–738.

    Article  PubMed  CAS  Google Scholar 

  30. Pitcher MH, Price TJ, Entrena JM, Cervero F. Spinal NKCC1 blockade inhibits TRPV1-dependent referred allodynia. Mol Pain 2007, 3: 17.

    Article  PubMed  Google Scholar 

  31. Yu L, Yang F, Luo H, Liu FY, Han JS, Xing GG, et al. The role of TRPV1 in different subtypes of dorsal root ganglion neurons in rat chronic inflammatory nociception induced by complete Freund’s adjuvant. Mol Pain 2008, 4: 61.

    Article  PubMed  Google Scholar 

  32. Walker KM, Urban L, Medhurst SJ, Patel S, Panesar M, Fox AJ, et al. The VR1 antagonist capsazepine reverses mechanical hyperalgesia in models of inflammatory and neuropathic pain. J Pharmacol Exp Ther 2003, 304: 56–62.

    Article  PubMed  CAS  Google Scholar 

  33. Watabiki T, Kiso T, Kuramochi T, Yonezawa K, Tsuji N, Kohara A, et al. Amelioration of neuropathic pain by novel transient receptor potential vanilloid 1 antagonist AS1928370 in rats without hyperthermic effect. J Pharmacol Exp Ther 2011, 336: 743–750.

    Article  PubMed  CAS  Google Scholar 

  34. Yamamoto W, Sugiura A, Nakazato-Imasato E, Kita Y. Characterization of primary sensory neurons mediating static and dynamic allodynia in rat chronic constriction injury model. J Pharm Pharmacol 2008, 60: 717–722.

    Article  PubMed  CAS  Google Scholar 

  35. Gavva NR, Tamir R, Qu Y, Klionsky L, Zhang TJ, Immke D, et al. AMG 9810 [(E)-3-(4-t-butylphenyl)-N-(2,3-dihydrobenzo[b][1,4] dioxin-6-yl)acrylamide], a novel vanilloid receptor 1 (TRPV1) antagonist with antihyperalgesic properties. J Pharmacol Exp Ther 2005, 313: 474–484.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Pain Research Center, Department of Anesthesiology, University of Cincinnati College of Medicine, Cincinnati, Ohio, 45267-0531, USA

    Fei Dong, Yi-Ru Du, Wenrui Xie, Judith A. Strong & Jun-Ming Zhang

  2. Department of Orthopedic Surgery, The Second Affiliated Hospital, School of Medicine, Xi’an Jiaotong University, Xi’an, 710004, China

    Fei Dong & Xi-Jing He

Authors
  1. Fei Dong
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yi-Ru Du
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Wenrui Xie
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Judith A. Strong
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xi-Jing He
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jun-Ming Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Xi-Jing He or Jun-Ming Zhang.

Additional information

These authors contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Dong, F., Du, YR., Xie, W. et al. Increased function of the TRPV1 channel in small sensory neurons after local inflammation or in vitro exposure to the pro-inflammatory cytokine GRO/KC. Neurosci. Bull. 28, 155–164 (2012). https://doi.org/10.1007/s12264-012-1208-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12264-012-1208-8

Keywords

Search

Navigation