Skip to main content
Log in

Desensitization of cold- and menthol-sensitive rat dorsal root ganglion neurones by inflammatory mediators

  • Research Article
  • Published:
Experimental Brain Research Aims and scope Submit manuscript

Abstract

The interaction between cold sensitivity and inflammation in mammals is not entirely understood. We have used adult rat dorsal root ganglion neurones in primary culture together with calcium microfluorimetry to assess the effects of selected inflammatory mediators on cold responses of cold- and menthol-sensitive (most likely TRPM8-expressing) neurones. We observed a high degree of functional co-expression of TRPM8, the receptors for the inflammatory agents bradykinin, prostaglandin E2 and histamine, and TRPA1 in cultured sensory neurones. Treatment with either bradykinin or prostaglandin E2 led to a reduction in the amplitude of the response to cooling and shifted the threshold temperature to colder values, and we provide evidence for a role of protein kinases C and A, respectively, in mediating these effects. In both cases the effects were mainly restricted to the subgroups of cold- and menthol-sensitive cells which had responded to the application of the inflammatory agents at basal temperature. This desensitization of cold-sensitive neurones may enhance inflammatory pain by removing the analgesic effects of gentle cooling.

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

Access this article

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

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Abbreviations

DRG:

Dorsal root ganglia

CMS:

Cold- and menthol-sensitive neurones

BK:

Bradykinin

PGE2 :

Prostaglandin E2

HA:

Histamine

CA:

Cinnamon aldehyde

PKA:

Protein kinase A

PKC:

Protein kinase C

8-Br-cAMP:

8 Bromo cyclic AMP

References

  • Abe J, Hosokawa H, Sawada Y, Matsumura K, Kobayashi S (2005) Ca(2+)-dependent PKC activation mediates menthol-induced desensitization of transient receptor potential M8. Neurosci Lett 397(1–2):140–144

    PubMed  Google Scholar 

  • Babes A, Zorzon D, Reid G (2004) Two populations of cold-sensitive neurons in rat dorsal root ganglia and their modulation by nerve growth factor. Eur J Neurosci 20(9):2276–2282

    Article  PubMed  Google Scholar 

  • Bandell M, Story GM, Hwang SW, Viswanath V, Eid SR, Petrus MJ, Earley TJ, Patapoutian A (2004) Noxious cold ion channel TRPA1 is activated by pungent compounds and bradykinin. Neuron 41(6):849–857

    Article  PubMed  CAS  Google Scholar 

  • Bautista DM, Jordt SE, Nikai T, Tsuruda PR, Read AJ, Poblete J, Yamoah EN, Basbaum AI, Julius D (2006) TRPA1 mediates the inflammatory actions of environmental irritants and proalgesic agents. Cell 124(6):1269–1282

    Article  PubMed  CAS  Google Scholar 

  • Bhave G, Zhu W, Wang H, Brasier DJ, Oxford GS, Gereau RW 4th (2002) cAMP-dependent protein kinase regulates desensitization of the capsaicin receptor (VR1) by direct phosphorylation. Neuron 35(4):721–731

    Article  PubMed  CAS  Google Scholar 

  • Caterina MJ, Schumacher MA, Tominaga M, Rosen TA, Levine JD, Julius D (1997) The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature 389(6653):816–824

    Article  PubMed  CAS  Google Scholar 

  • Caterina MJ, Leffler A, Malmberg AB, Martin WJ, Trafton J, Peterson-Zeitz KR, Koltzenburg M, Basbaum AI, Julius D (2000) Impaired nociception and pain sensation in mice lacking the capsaicin receptor. Science 288(5464):306–313

    Article  PubMed  CAS  Google Scholar 

  • Cesare P, McNaughton P (1996) A novel heat-activated current in nociceptive neurons and its sensitization by bradykinin. Proc Natl Acad Sci USA 93(26):15435–15439

    Article  PubMed  CAS  Google Scholar 

  • Cesare P, Dekker LV, Sardini A, Parker PJ, McNaughton PA (1999) Specific involvement of PKC-epsilon in sensitization of the neuronal response to painful heat. Neuron 23(3):617–624

    Article  PubMed  CAS  Google Scholar 

  • Chuang HH, Prescott ED, Kong H, Shields S, Jordt SE, Basbaum AI, Chao MV, Julius D (2001) Bradykinin and nerve growth factor release the capsaicin receptor from PtdIns(4,5)P2-mediated inhibition. Nature 411(6840):957–962

    Article  PubMed  CAS  Google Scholar 

  • Davis JB, Gray J, Gunthorpe MJ, Hatcher JP, Davey PT, Overend P, Harries MH, Latcham J, Clapham C, Atkinson K, Hughes SA, Rance K, Grau E, Harper AJ, Pugh PL, Rogers DC, Bingham S, Randall A, Sheardown SA (2000) Vanilloid receptor-1 is essential for inflammatory thermal hyperalgesia. Nature 405(6783):183–187

    Article  PubMed  CAS  Google Scholar 

  • Hucho TB, Dina OA, Levine JD (2005) Epac mediates a cAMP-to-PKC signaling in inflammatory pain: an isolectin B4(+) neuron-specific mechanism. J Neurosci 25(26):6119–6126

    Article  PubMed  CAS  Google Scholar 

  • Jordt SE, Bautista DM, Chuang HH, McKemy DD, Zygmunt PM, Hogestatt ED, Meng ID, Julius D (2004) Mustard oils and cannabinoids excite sensory nerve fibres through the TRP channel ANKTM1. Nature 427(6971):260–265

    Article  PubMed  CAS  Google Scholar 

  • Kasai M, Kumuzawa T, Mizumura K (1998) Nerve growth factor increases sensitivity to bradykinin, mediated through B2 receptors, in capsaicin-sensitive small neurons cultured from rat dorsal root ganglia. Neurosci Res 32(3):231–239

    Article  PubMed  CAS  Google Scholar 

  • Kim BM, Lee SH, Shim WS, Oh U (2004) Histamine-induced Ca(2+) influx via the PLA(2)/lipoxygenase/TRPV1 pathway in rat sensory neurons. Neurosci Lett 361(1–3):159–162

    Article  PubMed  CAS  Google Scholar 

  • Liu B, Qin F (2005) Functional control of cold- and menthol-sensitive TRPM8 ion channels by phosphatidylinositol 4,5-bisphosphate. J Neurosci 25(7):1674–1681

    Article  PubMed  CAS  Google Scholar 

  • Lopshire JC, Nicol GD (1998) The cAMP transduction cascade mediates the prostaglandin E2 enhancement of the capsaicin-elicited current in rat sensory neurons: whole-cell and single-channel studies. J Neurosci 18(16):6081–6092

    PubMed  CAS  Google Scholar 

  • McKemy DD, Nehausser WM, Julius D (2002) Identification of a cold receptor reveals a general role for TRP channels in thermosensation. Nature 416(6876):52–58

    Article  PubMed  CAS  Google Scholar 

  • Nagata K, Duggan A, Kumar G, Garcia-Anoveros J (2005) Nociceptor and hair cell transducer properties of TRPA1, a channel for pain and hearing. J Neurosci 25(16):4052–4061

    Article  PubMed  CAS  Google Scholar 

  • Nakayama Y, Omote K, Kawamata T, Namiki A (2004) Role of prostaglandin receptor subtype EP1 in prostaglandin E2-induced nociceptive transmission in the rat spinal dorsal horn. Brain Res 1010(1–2):62–68

    Article  PubMed  CAS  Google Scholar 

  • Obata K, Katsura H, Mizushima T, Yamanaka H, Kobayashi K, Dai Y, Fukuoka T, Tokunaga A, Tominaga M, Noguchi K (2005) TRPA1 induced in sensory neurons contributes to cold hyperalgesia after inflammation and nerve injury. J Clin Invest 115(9):2393–2401

    Article  PubMed  CAS  Google Scholar 

  • Peier AM, Moqrich A, Hergarden AC, Reeve AJ, Andersson DA, Story GM, Earley TJ, Dragoni I, McIntyre P, Bevan S, Patapoutian A (2002) A TRP channel that senses cold stimuli and menthol. Cell 108(5):705–715

    Article  PubMed  CAS  Google Scholar 

  • Petersen M, Klusch A, Eckert A (1998a) The proportion of isolated rat dorsal root ganglion neurons responding to bradykinin increases with time in culture. Neurosci Lett 252:143–146

    Article  CAS  Google Scholar 

  • Petersen M, Segond von Banchet G, Heppelmann B, Koltzenburg M (1998b) Nerve growth factor regulates the expression of bradykinin binding sites on adult sensory neurons via the neurotrophin receptor p75. Neuroscience 83(1):161–168

    Article  CAS  Google Scholar 

  • Premkumar LS, Rainsinghani M, Pingle SC, Long C, Pimentel F (2005) Downregulation of transient receptor potential melastatin 8 by protein kinase C-mediated dephosphorylation. J Neurosci 25(49):11322–11329

    Article  PubMed  CAS  Google Scholar 

  • Reid G, Amuzescu B, Zech E, Flonta ML (2001) A system for applying rapid warming and cooling stimuli to cells during patch clamp recording or ion imaging. J Neurosci Methods 111(1):1–8

    Article  PubMed  CAS  Google Scholar 

  • Reid G, Babes A, Pluteanu F (2002) A cold- and menthol-activated current in rat dorsal root ganglion neurones: properties and role in cold transduction. J Physiol 545(Pt 2):595–614

    Article  PubMed  CAS  Google Scholar 

  • Rohacs T, Lopes CM, Michailidis I, Logothetis DE (2005) PI(4,5)P2 regulates the activation and desensitization of TRPM8 channels through the TRP domain. Nat Neurosci 8(5):626–634

    Article  PubMed  CAS  Google Scholar 

  • Story GM, Peier AM, Reeve AJ, Eid SR, Mosbacher J, Hricik TR, Earley TJ, Hergarden AC, Andersson DA, Hwang SW, McIntyre P, Jegla T, Bevan S, Patapoutian A (2003) ANKTM1, a TRP-like channel expressed in nociceptive neurons, is activated by cold temperatures. Cell 112(6):819–829

    Article  PubMed  CAS  Google Scholar 

  • Sugiura T, Tominaga M, Katsuya H, Mizumura K (2002) Bradykinin lowers the threshold temperature for heat activation of vanilloid receptor 1. J Neurophysiol 88(1):544–548

    PubMed  CAS  Google Scholar 

  • Vellani V, Mapplebeck S, Moriondo A, Davis JB, McNaughton PA (2001) Protein kinase C activation potentiates gating of the vanilloid receptor VR1 by capsaicin, protons, heat and anandamide. J Physiol 534(Pt 3):813–825

    Article  PubMed  CAS  Google Scholar 

  • Vellani V, Zachrisson O, McNaughton P (2004) Functional bradykinin B1 receptors are expressed in nociceptive neurones and are upregulated by the neurotrophin GDNF. J Physiol 560(2):391–401

    Article  PubMed  CAS  Google Scholar 

  • Viana F, de la Peña E, Belmonte C (2002) Specificity of cold thermotransduction is determined by differential ionic channel expression. Nat Neurosci 5(3):254–260

    Article  PubMed  CAS  Google Scholar 

  • Xing H, Ling J, Chen M, Gu JG (2006) Chemical and cold sensitivity of two distinct populations of TRPM8-expressing somatosensory neurons. J Neurophysiol 95(2):1221–1230

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We are grateful to Prof. Peter Reeh for valuable comments on the manuscript and helpful discussions. We thank Prof. Maria-Luiza Flonta for constant support, Dr. Eva Lörinczi and Dr. Klaus Fendler for logistic help and Cristian Neacşu for technical help. Funding was from the Volkswagen Foundation, the Romanian Research Council (CNCSIS), the Romanian Ministry for Education and Research through its Excellence Grants and the Physiological Society. A.B. acknowledges the Humboldt Foundation for financial support.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Alexandru Babes.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Linte, R.M., Ciobanu, C., Reid, G. et al. Desensitization of cold- and menthol-sensitive rat dorsal root ganglion neurones by inflammatory mediators. Exp Brain Res 178, 89–98 (2007). https://doi.org/10.1007/s00221-006-0712-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00221-006-0712-3

Keywords

Navigation