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