Experimental Brain Research

, Volume 196, Issue 1, pp 45–52 | Cite as

Regulation of firing frequency in nociceptive neurons by pro-inflammatory mediators

  • Aliakmal Momin
  • Peter A. McNaughton


Nociceptive neurons generate trains of action potentials in response to painful stimuli, and the frequency of firing signals the intensity of the pain. Pro-inflammatory mediators such as prostaglandin E 2 (PGE2) enhance the sensation of pain by increasing the frequency of action potential firing in response to a given level of painful stimulus. The mechanism by which the firing frequency is enhanced is discussed in the present review. One hypothesis proposes that the threshold for action potential initiation is lowered because the activation curve of a nociceptor-specific voltage-activated Na current, NaV1.8, is shifted to more negative values by PGE2. Recent measurements in our lab show, however, that the action potential threshold in fact changes little when AP firing is accelerated by PGE2. The enhanced firing is, however, abolished by a blocker of an inward current activated by hyperpolarisation, called I h. The voltage sensitivity of I h shifts in the positive direction in small nociceptive neurons when they are exposed to pro-inflammatory mediators, such as PGE2, which activate adenylate cyclase and therefore increase levels of cAMP. By this mechanism the inward current between the resting membrane potential and the threshold for firing of action potentials is enhanced, and the rate of depolarisation in the interval between action potentials is therefore increased. We conclude that the major mechanism responsible for increasing action potential firing following tissue damage or metabolic stress is the hyperpolarisation-activated inward current, I h, and that other mechanisms play at most a minor role.


Pain Sensory transduction Action potential Prostaglandin 


  1. Akopian AN, Sivilotti L, Wood JN (1996) A tetrodotoxin-resistant voltage-gated sodium channel expressed by sensory neurons. Nature 379:257–262PubMedCrossRefGoogle Scholar
  2. Akopian AN, Souslova V, England S, Okuse K, Ogata N, Ure J, Smith A, Kerr BJ, McMahon SB, Boyce S, Hill R, Stanfa LC, Dickenson AH, Wood JN (1999) The tetrodotoxin-resistant sodium channel SNS has a specialized function in pain pathways. Nat Neurosci 2:541–548PubMedCrossRefGoogle Scholar
  3. Amaya F, Wang H, Costigan M, Allchorne AJ, Hatcher JP, Egerton J, Stean T, Morisset V, Grose D, Gunthorpe MJ, Chessell IP, Tate S, Green PJ, Woolf CJ (2006) The voltage-gated sodium channel Na(v)1.9 is an effector of peripheral inflammatory pain hypersensitivity. J Neurosci 26:12852–12860PubMedCrossRefGoogle Scholar
  4. Belmonte C, Giraldez F (1981) Responses of cat corneal sensory receptors to mechanical and thermal stimulation. J Physiol 321:355–368PubMedGoogle Scholar
  5. Cesare P, McNaughton PA (1996) A novel heat-activated current in nociceptive neurons, and its sensitization by bradykinin. Proc Natl Acad Sci USA 93:15435–15439PubMedCrossRefGoogle Scholar
  6. 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 23:617–624PubMedCrossRefGoogle Scholar
  7. Chan CS, Shigemoto R, Mercer JN, Surmeier DJ (2004) HCN2 and HCN1 channels govern the regularity of autonomous pacemaking and synaptic resetting in globus pallidus neurons. J Neurosci 24:9921–9932PubMedCrossRefGoogle Scholar
  8. Chaplan SR, Guo HQ, Lee DH, Luo L, Liu C, Kuei C, Velumian AA, Butler MP, Brown SM, Dubin AE (2003) Neuronal hyperpolarization-activated pacemaker channels drive neuropathic pain. J Neurosci 23:1169–1178PubMedGoogle Scholar
  9. DiFrancesco D (1993) Pacemaker mechanisms in cardiac tissue. Annu Rev Physiol 55:455–472PubMedCrossRefGoogle Scholar
  10. DiFrancesco D, Ojeda C (1980) Properties of the current if in the sino-atrial node of the rabbit compared with those of the current iK, in Purkinje fibres. J Physiol 308:353–367PubMedGoogle Scholar
  11. DiFrancesco D, Tortora P (1991) Direct activation of cardiac pacemaker channels by intracellular cyclic AMP. Nature 351:145–147PubMedCrossRefGoogle Scholar
  12. Doan TN, Stephans K, Ramirez AN, Glazebrook PA, Andresen MC, Kunze DL (2004) Differential distribution and function of hyperpolarization-activated channels in sensory neurons and mechanosensitive fibers. J Neurosci 24:3335–3343PubMedCrossRefGoogle Scholar
  13. Dray A (1995) Inflammatory mediators of pain. Br J Anaesth 75:125–131PubMedGoogle Scholar
  14. Elliott AA, Elliott JR (1993) Characterization of TTX-sensitive and TTX-resistant sodium currents in small cells from adult rat dorsal root ganglia. J Physiol 463:39–56PubMedGoogle Scholar
  15. England S, Bevan S, Docherty RJ (1996) PGE2 modulates the tetrodotoxin-resistant sodium current in neonatal rat dorsal root ganglion neurones via the cyclic AMP-protein kinase A cascade. J Physiol 495:429–440PubMedGoogle Scholar
  16. Evans AR, Vasko MR, Nicol GD (1999) The cAMP transduction cascade mediates the PGE2-induced inhibition of potassium currents in rat sensory neurones. J Physiol 516:163–178PubMedCrossRefGoogle Scholar
  17. Ferreira SH (1972) Prostaglandins, aspirin-like drugs and analgesia. Nat New Biol 240:200–203PubMedCrossRefGoogle Scholar
  18. Fitzgerald EM, Okuse K, Wood JN, Dolphin AC, Moss SJ (1999) cAMP-dependent phosphorylation of the tetrodotoxin-resistant voltage-dependent sodium channel SNS. J Physiol 516:433–446PubMedCrossRefGoogle Scholar
  19. Gold MS, Reichling DB, Shuster MJ, Levine JD (1996) Hyperalgesic agents increase a tetrodotoxin-resistant Na+ current in nociceptors. Proc Natl Acad Sci USA 93:1108–1112PubMedCrossRefGoogle Scholar
  20. Gold MS, Levine JD, Correa AM (1998) Modulation of TTX-R I(Na) by PKC and PKA and their role in PGE2- induced sensitization of rat sensory neurons in vitro. J Neurosci 18:10345–10355PubMedGoogle Scholar
  21. Harper AA, Lawson SN (1985) Conduction velocity is related to morphological cell type in rat dorsal root ganglion neurones. J Physiol 359:31–46PubMedGoogle Scholar
  22. Huang J, Zhang X, McNaughton PA (2006a) Inflammatory pain: the cellular basis of heat hyperalgesia. Curr Neuropharmacol 4:197–206PubMedCrossRefGoogle Scholar
  23. Huang J, Zhang X, McNaughton PA (2006b) Modulation of temperature-sensitive TRP channels. Semin Cell Dev Biol 17:638–645PubMedCrossRefGoogle Scholar
  24. Ingram SL, Williams JT (1994) Opioid inhibition of I(h) via adenylyl cyclase. Neuron 13:179–186PubMedCrossRefGoogle Scholar
  25. Ingram SL, Williams JT (1996) Modulation of the hyperpolarisation-activated current (I(h)) by cyclic nucleotides in guinea-pig primary afferent neurons. J Physiol 492:97–106PubMedGoogle Scholar
  26. Jiang X, Zhang YH, Clark JD, Tempel BL, Nicol GD (2003) Prostaglandin E2 inhibits the potassium current in sensory neurons from hyperalgesic Kv1.1 knockout mice. Neuroscience 119:65–72PubMedCrossRefGoogle Scholar
  27. Kajander KC, Wakisaka S, Bennett GJ (1992) Spontaneous discharge originates in the dorsal root ganglion at the onset of a painful peripheral neuropathy in the rat. Neurosci Lett 138:225–228PubMedCrossRefGoogle Scholar
  28. Kaupp UB, Seifert R (2001) Molecular diversity of pacemaker ion channels. Annu Rev Physiol 63:235–257PubMedCrossRefGoogle Scholar
  29. Kerr BJ, Souslova V, McMahon SB, Wood JN (2001) A role for the TTX-resistant sodium channel Nav 1.8 in NGF-induced hyperalgesia, but not neuropathic pain. Neuroreport 12:3077–3080PubMedCrossRefGoogle Scholar
  30. Lawson SN (2002) Phenotype and function of somatic primary afferent nociceptive neurones with C-, Adelta- or Aalpha/beta-fibres. Exp Physiol 87:239–244PubMedCrossRefGoogle Scholar
  31. Ludwig A, Budde T, Stieber J, Moosmang S, Wahl C, Holthoff K, Langebartels A, Wotjak C, Munsch T, Zong X, Feil S, Feil R, Lancel M, Chien KR, Konnerth A, Pape HC, Biel M, Hofmann F (2003) Absence epilepsy and sinus dysrhythmia in mice lacking the pacemaker channel HCN2. EMBO J 22:216–224PubMedCrossRefGoogle Scholar
  32. Luo L, Chang L, Brown SM, Ao H, Lee DH, Higuera ES, Dubin AE, Chaplan SR (2007) Role of peripheral hyperpolarization-activated cyclic nucleotide-modulated channel pacemaker channels in acute and chronic pain models in the rat. Neuroscience 144:1477–1485PubMedCrossRefGoogle Scholar
  33. Matsuyoshi H, Masuda N, Chancellor MB, Erickson VL, Hirao Y, de Groat WC, Wanaka A, Yoshimura N (2006) Expression of hyperpolarization-activated cyclic nucleotide-gated cation channels in rat dorsal root ganglion neurons innervating urinary bladder. Brain Res 1119:115–123PubMedCrossRefGoogle Scholar
  34. McCormick DA, Pape HC (1990) Properties of a hyperpolarization-activated cation current and its role in rhythmic oscillation in thalamic relay neurones. J Physiol 431:291–318PubMedGoogle Scholar
  35. McKemy DD, Neuhausser WM, Julius D (2002) Identification of a cold receptor reveals a general role for TRP channels in thermosensation. Nature 416:52–58PubMedCrossRefGoogle Scholar
  36. McQuay HJ, Tramer M, Nye BA, Carroll D, Wiffen PJ, Moore RA (1996) A systematic review of antidepressants in neuropathic pain. Pain 68:217–227PubMedCrossRefGoogle Scholar
  37. Momin A, Cadiou H, Mason A, McNaughton PA (2008) Role of the hyperpolarization-activated current Ih in somatosensory neurons. J Physiol 586:5911–5929PubMedCrossRefGoogle Scholar
  38. Moosmang S, Stieber J, Zong X, Biel M, Hofmann F, Ludwig A (2001) Cellular expression and functional characterization of four hyperpolarization-activated pacemaker channels in cardiac and neuronal tissues. Eur J Biochem 268:1646–1652PubMedCrossRefGoogle Scholar
  39. Moriyama T, Higashi T, Togashi K, Iida T, Segi E, Sugimoto Y, Tominaga T, Narumiya S, Tominaga M (2005) Sensitization of TRPV1 by EP1 and IP reveals peripheral nociceptive mechanism of prostaglandins. Mol Pain 1:3PubMedCrossRefGoogle Scholar
  40. Nassar MA, Stirling LC, Forlani G, Baker MD, Matthews EA, Dickenson AH, Wood JN (2004) Nociceptor-specific gene deletion reveals a major role for Nav1.7 (PN1) in acute and inflammatory pain. Proc Natl Acad Sci USA 101:12706–12711PubMedCrossRefGoogle Scholar
  41. Nassar MA, Baker MD, Levato A, Ingram R, Mallucci G, McMahon SB, Wood JN (2006) Nerve injury induces robust allodynia and ectopic discharges in Nav1.3 null mutant mice. Mol Pain 2:33PubMedCrossRefGoogle Scholar
  42. Nicol GD, Vasko MR, Evans AR (1997) Prostaglandins suppress an outward potassium current in embryonic rat sensory neurons. J Neurophysiol 77:167–176PubMedGoogle Scholar
  43. Nolan MF, Malleret G, Lee KH, Gibbs E, Dudman JT, Santoro B, Yin D, Thompson RF, Siegelbaum SA, Kandel ER, Morozov A (2003) The hyperpolarization-activated HCN1 channel is important for motor learning and neuronal integration by cerebellar Purkinje cells. Cell 115:551–564PubMedCrossRefGoogle Scholar
  44. Obreja O, Klusch A, Ponelies N, Schmelz M, Petersen M (2008) A subpopulation of capsaicin-sensitive porcine dorsal root ganglion neurons is lacking hyperpolarization-activated cyclic nucleotide-gated channels. Eur J Pain 12:775–789PubMedCrossRefGoogle Scholar
  45. Pape HC (1996) Queer current and pacemaker: the hyperpolarization-activated cation current in neurons. Annu Rev Physiol 58:299–327PubMedCrossRefGoogle Scholar
  46. Pape HC, McCormick DA (1989) Noradrenaline and serotonin selectively modulate thalamic burst firing by enhancing a hyperpolarization-activated cation current. Nature 340:715–718PubMedCrossRefGoogle Scholar
  47. Priest BT, Murphy BA, Lindia JA, Diaz C, Abbadie C, Ritter AM, Liberator P, Iyer LM, Kash SF, Kohler MG, Kaczorowski GJ, Macintyre DE, Martin WJ (2005) Contribution of the tetrodotoxin-resistant voltage-gated sodium channel NaV1.9 to sensory transmission and nociceptive behavior. Proc Natl Acad Sci USA 102:9382–9387PubMedCrossRefGoogle Scholar
  48. Sheen K, Chung JM (1993) Signs of neuropathic pain depend on signals from injured nerve fibers in a rat model. Brain Res 610:62–68PubMedCrossRefGoogle Scholar
  49. Tsay D, Dudman JT, Siegelbaum SA (2007) HCN1 channels constrain synaptically evoked Ca2+ spikes in distal dendrites of CA1 pyramidal neurons. Neuron 56:1076–1089PubMedCrossRefGoogle Scholar
  50. Tu H, Deng L, Sun Q, Yao L, Han JS, Wan Y (2004) Hyperpolarization-activated, cyclic nucleotide-gated cation channels: roles in the differential electrophysiological properties of rat primary afferent neurons. J Neurosci Res 76:713–722PubMedCrossRefGoogle Scholar
  51. Viana F, De La PE, Belmonte C (2002) Specificity of cold thermotransduction is determined by differential ionic channel expression. Nat Neurosci 5:254–260PubMedCrossRefGoogle Scholar
  52. Yao H, Donnelly DF, Ma C, LaMotte RH (2003) Upregulation of the hyperpolarization-activated cation current after chronic compression of the dorsal root ganglion. J Neurosci 23:2069–2074PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  1. 1.Department of PharmacologyUniversity of CambridgeCambridgeUK

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