Advertisement

Long-Term Potentiation in Superficial Spinal Dorsal Horn: A Pain Amplifier

  • Ruth Drdla
  • Jürgen Sandkühler
Chapter

Abstract

Long-term potentiation of synaptic strength (LTP) is one of the most intensively studied models of lasting signal amplification in the nervous systems. LTP has also been identified at synapses between small primary afferent Aδ- or C-fibres, many of which are nociceptive, and 2nd order neurons in superficial spinal dorsal horn. In the present chapter we review fundamental properties of spinal LTP and we describe different induction protocols including electrical nerve stimulation, acute nerve injury and noxious stimulation such as capsaicin or formalin intraplantar injections. The presently known signal transduction pathways leading to LTP in pain pathways include activation of NMDA receptor and NK1 receptors for substance P, opening of T-type voltage-gated calcium channel, release of Ca2+ from intracellular stores, as well as activation of PKC and CaMKII. These signalling pathways are similar to those leading to hyperalgesia. The converging and independent evidence summarized in this chapter suggests that LTP at the first synapse in pain pathways may underlie various forms of hyperalgesia following trauma, inflammation or nerve injury.

Keywords

Conditioning Stimulus Chronic Constriction Injury Synaptic Strength Spare Nerve Injury High Frequency Stimulation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Abbreviations

CaMKII

Ca2+ calmodulin dependent kinase II

CREB

cAMP-response element binding protein

GABA

gamma-aminobutyric acid

GLT1

glutamate transporter 1

i.v.

intravenous

IASP

International Association for the Study of Pain

inhal.

inhalation

IP3

inositol triphosphate

LTD

long-term depression

LTP

long-term potentiation

MAPK

mitogen activated kinase

mGluR

metabotropic glutamate receptor

n.t.

not tried

NK1-R

neurokinin 1 receptor

NMDA

N-methyl-D-aspartate

NMDAR

N-methyl-D-aspartate-receptor

NO

nitric oxide

PKA

protein kinase A

PKC

protein kinase C

PLC

phospholipase C

superf.

superfusion

VDCC

voltage-dependent Ca2+ channel

References

  1. Afrah AW, Fiskå A, Gjerstad J et al (2002) Spinal substance P release in vivo during the induction of long-term potentiation in dorsal horn neurons. Pain 96:49–55PubMedCrossRefGoogle Scholar
  2. Azkue JJ, Liu X-G, Zimmermann M et al (2003) Induction of long-term potentiation of C fibre-evoked spinal field potentials requires recruitment of group I, but not group II/III metabotropic glutamate receptors. Pain 106:373–379PubMedCrossRefGoogle Scholar
  3. Basbaum AI, Fields HL (1978) Endogenous pain control mechanisms: review and hypothesis. Ann Neurol 4:451–462PubMedCrossRefGoogle Scholar
  4. Benrath J, Brechtel C, Martin E et al (2004) Low doses of fentanyl block central sensitization in the rat spinal cord in vivo. Anesthesiology 100:1545–1551PubMedCrossRefGoogle Scholar
  5. Benrath J, Kempf C, Georgieff M et al (2007) Xenon blocks the induction of synaptic long-term potentiation in pain pathways in the rat spinal cord in vivo. Anesth Analg 104:106–111PubMedCrossRefGoogle Scholar
  6. Bi G-Q , Poo M-M (1998) Synaptic modifications in cultured hippocampal neurons: dependence on spike timing, synaptic strength, and postsynaptic cell type. J Neurosci 18:10464–10472PubMedGoogle Scholar
  7. Coull JAM, Beggs S, Boudreau D et al (2005) BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain. Nature 438:1017–1021PubMedCrossRefGoogle Scholar
  8. Coull JAM, Boudreau D, Bachand K et al (2003) Trans-synaptic shift in anion gradient in spinal lamina I neurons as a mechanism of neuropathic pain. Nature 424:938–942PubMedCrossRefGoogle Scholar
  9. Drdla R, Sandkühler J (2008) Long-term potentiation at C-fibre synapses by low-level presynaptic activity in vivo. Mol Pain 4:18PubMedCrossRefGoogle Scholar
  10. Ge Y-X, Xin W-J, Hu N-W et al (2006) Clonidine depresses LTP of C-fiber evoked field potentials in spinal dorsal horn via NO-cGMP pathway. Brain Res 1118:58–65PubMedCrossRefGoogle Scholar
  11. Handwerker HO, Anton F, Reeh PW (1987) Discharge patterns of afferent cutaneous nerve fibers from the rat's tail during prolonged noxious mechanical stimulation. Exp Brain Res 65:493–504PubMedCrossRefGoogle Scholar
  12. Haugan F, Rygh LJ, Tjølsen A (2008) Ketamine blocks enhancement of spinal long-term potentiation in chronic opioid treated rats. Acta Anaesthesiol Scand 52:681–687PubMedCrossRefGoogle Scholar
  13. Hu N-W, Zhang H-M, Hu X-D et al (2003) Protein synthesis inhibition blocks the late-phase LTP of C-fiber evoked field potentials in rat spinal dorsal horn. J Neurophysiol 89:2354–2359PubMedCrossRefGoogle Scholar
  14. Hu X-D, Ge Y-X, Hu N-W et al (2006) Diazepam inhibits the induction and maintenance of LTP of C-fiber evoked field potentials in spinal dorsal horn of rats. Neuropharmacology 50:238–244PubMedCrossRefGoogle Scholar
  15. Ikeda H, Heinke B, Ruscheweyh R et al (2003) Synaptic plasticity in spinal lamina I projection neurons that mediate hyperalgesia. Science 299:1237–1240PubMedCrossRefGoogle Scholar
  16. Ikeda H, Murase K (2004) Glial nitric oxide-mediated long-term presynaptic facilitation revealed by optical imaging in rat spinal dorsal horn. J Neurosci 24:9888–9896PubMedCrossRefGoogle Scholar
  17. Ikeda H, Stark J, Fischer H et al (2006) Synaptic amplifier of inflammatory pain in the spinal dorsal horn. Science 312:1659–1662PubMedCrossRefGoogle Scholar
  18. Ikeda H, Tsuda M, Inoue K et al (2007) Long-term potentiation of neuronal excitation by neuron-glia interactions in the rat spinal dorsal horn. Eur J Neurosci 25:1297–1306PubMedCrossRefGoogle Scholar
  19. Klein T, Magerl W, Hopf H-C et al (2004) Perceptual correlates of nociceptive long-term potentiation and long-term depression in humans. J Neurosci 24:964–971PubMedCrossRefGoogle Scholar
  20. Klein T, Magerl W, Nickel U et al (2007a) Effects of the NMDA-receptor antagonist ketamine on perceptual correlates of long-term potentiation within the nociceptive system. Neuropharmacology 52:655–661PubMedCrossRefGoogle Scholar
  21. Klein T, Magerl W, Treede R-D (2007b) Perceptual correlate of nociceptive long-term potentiation (LTP) in humans shares the time course of early-LTP(LTP1). J Neurophysiol 96:3551–3555CrossRefGoogle Scholar
  22. Klein T, Stahn S, Magerl W et al (2008) The role of heterosynaptic facilitation in long-term potentiation (LTP) of human pain sensation. Pain 139:507–519Google Scholar
  23. Lang S, Klein T, Magerl W et al (2007) Modality-specific sensory changes in humans after the induction of long-term potentiation (LTP) in cutaneous nociceptive pathways. Pain 128:254–263PubMedCrossRefGoogle Scholar
  24. Lever IJ, Bradbury EJ, Cunningham JR et al (2001) Brain-derived neurotrophic factor is released in the dorsal horn by distinctive patterns of afferent fiber stimulation. J Neurosci 21:4469–4477PubMedGoogle Scholar
  25. Lieberman DN, Mody I (1998) Substance P enhances NMDA channel function in hippocampal dentate gyrus granule cells. J Neurophysiol 80:113–119PubMedGoogle Scholar
  26. Lisman J (1989) A mechanism for the Hebb and the anti-Hebb processes underlying learning and memory. Proc Natl Acad Sci USA 86:9574–9578PubMedCrossRefGoogle Scholar
  27. Lisman J, Raghavachari S (2006) A unified model of the presynaptic and postsynaptic changes during LTP at CA1 synapses. Sci STKE 2006:1–15CrossRefGoogle Scholar
  28. Lisman JE (2001) Three Ca2+ levels affect plasticity differently: the LTP zone, the LTD zone and no man's land. J Physiol 532:285–285PubMedCrossRefGoogle Scholar
  29. Liu X-G, Morton CR, Azkue JJ et al (1998) Long-term depression of C-fibre-evoked spinal field potentials by stimulation of primary afferent Aδ-fibres in the adult rat. Eur J Neurosci 10:3069–3075PubMedCrossRefGoogle Scholar
  30. Liu X-G, Sandkühler J (1997) Characterization of long-term potentiation of C-fiber-evoked potentials in spinal dorsal horn of adult rat: essential role of NK1 and NK2 receptors. J Neurophysiol 78:1973–1982PubMedGoogle Scholar
  31. Liu X-G, Sandkühler J (1998) Activation of spinal N-methyl-D-aspartate or neurokinin receptors induces long-term potentiation of spinal C-fibre-evoked potentials. Neuroscience 86:1209–1216PubMedCrossRefGoogle Scholar
  32. Liu X-G, Sandkühler J (1995) Long-term potentiation of C-fiber-evoked potentials in the rat spinal dorsal horn is prevented by spinal N-methyl-D-aspartic acid receptor blockage. Neurosci Lett 191:43–46PubMedCrossRefGoogle Scholar
  33. Liu Y-L, Zhou L-J, Hu N-W et al (2007) Tumor necrosis factor-α induces long-term potentiation of C-fiber evoked field potentials in spinal dorsal horn in rats with nerve injury: the role of NF-kappa B, JNK and p38 MAPK. Neuropharmacology 52:708–715PubMedCrossRefGoogle Scholar
  34. Ma J-Y, Zhao Z-Q (2002) The involvement of glia in long-term plasticity in the spinal dorsal horn of the rat. Neuroreport 13:1781–1784PubMedCrossRefGoogle Scholar
  35. Mantyh PW, Rogers SD, Honoré P et al (1997) Inhibition of hyperalgesia by ablation of lamina I spinal neurons expressing the substance P receptor. Science 278:275–279PubMedCrossRefGoogle Scholar
  36. Meller ST, Gebhart GF (1993) Nitric oxide (NO) and nociceptive processing in the spinal cord. Pain 52:127–136PubMedCrossRefGoogle Scholar
  37. Miletic G, Draganic P, Pankratz MT et al (2003) Muscimol prevents long-lasting potentiation of dorsal horn field potentials in rats with chronic constriction injury exhibiting decreased levels of the GABA transporter GAT-1. Pain 105:347–353PubMedCrossRefGoogle Scholar
  38. Miletic G, Miletic V (2000) Long-term changes in sciatic-evoked A-fiber dorsal horn field potentials accompany loose ligation of the sciatic nerve in rats. Pain 84:353–359PubMedCrossRefGoogle Scholar
  39. Miletic G, Miletic V (2001) Contribution of GABA-A receptors to metaplasticity in the spinal dorsal horn. Pain 90:157–162PubMedCrossRefGoogle Scholar
  40. Nichols ML, Allen BJ, Rogers SD et al (1999) Transmission of chronic nociception by spinal neurons expressing the substance P receptor. Science 286:1558–1561PubMedCrossRefGoogle Scholar
  41. Nishiyama M, Hong K, Mikoshiba K et al (2000) Calcium stores regulate the polarity and input specificity of synaptic modification. Nature 408:584–588PubMedCrossRefGoogle Scholar
  42. Pedersen LM, Gjerstad J (2008) Spinal cord long-term potentiation is attenuated by the NMDA-2B receptor antagonist Ro 25-6981. Acta Physiol (Oxf) 192:421–427CrossRefGoogle Scholar
  43. Petersen-Zeitz KR, Basbaum AI (1999) Second messengers, the substantia gelatinosa and injury-induced persistent pain. Pain Suppl 6:S5–12CrossRefGoogle Scholar
  44. Puig S, Sorkin LS (1996) Formalin-evoked activity in identified primary afferent fibers: systemic lidocaine suppresses phase-2 activity. Pain 64:345–355PubMedCrossRefGoogle Scholar
  45. Randic M, Jiang MC, Cerne R (1993) Long-term potentiation and long-term depression of primary afferent neurotransmission in the rat spinal cord. J Neurosci 13:5228–5241PubMedGoogle Scholar
  46. Rusin KI, Jiang MC, Cerne R et al (1993) Interactions between excitatory amino acids and tachykinins in the rat spinal dorsal horn. Brain Res Bull 30:329–338PubMedCrossRefGoogle Scholar
  47. Rygh LJ, Suzuki R, Rahman W et al (2006) Local and descending circuits regulate long-term potentiation and zif268 expression in spinal neurons. Eur J Neurosci 24:761–772PubMedCrossRefGoogle Scholar
  48. Sandkühler J (1996) The organization and function of endogenous antinociceptive systems. Prog Neurobiol 50:49–81PubMedGoogle Scholar
  49. Sandkühler J (2000a) Learning and memory in pain pathways. Pain 88:113–118PubMedCrossRefGoogle Scholar
  50. Sandkühler J (2000b) Long-lasting analgesia following TENS and acupuncture: Spinal mechanisms beyond gate control. In: Devor M, Rowbotham MC, Wiesenfeld-Hallin Z (ed) Proceedings of the 9th World Congress on Pain. IASP Press SeattleGoogle Scholar
  51. Sandkühler J, Chen JG, Cheng G et al (1997) Low-frequency stimulation of afferent Aδ-fibers induces long-term depression at primary afferent synapses with substantia gelatinosa neurons in the rat. J Neurosci 17:6483–6491PubMedGoogle Scholar
  52. Sandkühler J, Liu X (1998) Induction of long-term potentiation at spinal synapses by noxious stimulation or nerve injury. Eur J Neurosci 10:2476–2480PubMedCrossRefGoogle Scholar
  53. Schouenborg J (1984) Functional and topographical properties of field potentials evoked in rat dorsal horn by cutaneous C-fibre stimulation. J Physiol 356:169–192PubMedGoogle Scholar
  54. Suzuki R, Morcuende S, Webber M et al (2002) Superficial NK1-expressing neurons control spinal excitability through activation of descending pathways. Nat Neurosci 5:1319–1326PubMedCrossRefGoogle Scholar
  55. Terman GW, Eastman CL, Chavkin C (2001) Mu opiates inhibit long-term potentiation induction in the spinal cord slice. J Neurophysiol 85:485–494PubMedGoogle Scholar
  56. Vikman KS, Duggan AW, Siddall PJ (2003) Increased ability to induce long-term potentiation of spinal dorsal horn neurones in monoarthritic rats. Brain Res 990:51–57PubMedCrossRefGoogle Scholar
  57. Wang Z-Y, Zhang Y-Q, Zhao Z-Q (2006) Inhibition of tetanically sciatic stimulation-induced LTP of spinal neurons and Fos expression by disrupting glutamate transporter GLT-1. Neuropharmacology 51:764–772PubMedCrossRefGoogle Scholar
  58. Watkins LR, Maier SF (2002) Beyond neurons: evidence that immune and glial cells contribute to pathological pain states. Physiol Rev 82:981–1011PubMedGoogle Scholar
  59. Willis WD, Jr. (2001) Role of neurotransmitters in sensitization of pain responses. Ann NY Acad Sci 933:142–156PubMedCrossRefGoogle Scholar
  60. Xin W-J, Gong Q-J, Xu J-T et al (2006) Role of phosphorylation of ERK in induction and maintenance of LTP of the C-fiber evoked field potentials in spinal dorsal horn. J Neurosci Res 84:934–943PubMedCrossRefGoogle Scholar
  61. Xing G-G, Liu F-Y, Qu X-X et al (2007) Long-term synaptic plasticity in the spinal dorsal horn and its modulation by electroacupuncture in rats with neuropathic pain. Exp Neurol 208:323–332PubMedGoogle Scholar
  62. Yang H-W, Hu X-D, Zhang H-M et al (2004) Roles of CaMKII, PKA and PKC in the induction and maintenance of LTP of C-fiber evoked field potentials in rat spinal dorsal horn. J Neurophysiol 91:1122–1133PubMedCrossRefGoogle Scholar
  63. Yang H-W, Zhou L-J, Hu N-W et al (2005) Activation of spinal D1/D5 receptors induces late-phase LTP of c-fiber evoked field potentials in rat spinal dorsal horn. J Neurophysiol 94:961–967PubMedCrossRefGoogle Scholar
  64. Youn D-H, Royle G, Kolaj M et al (2008) Enhanced LTP of primary afferent neurotransmission in AMPA receptor GluR2-deficient mice. Pain 136:158–167PubMedCrossRefGoogle Scholar
  65. Zhang H-M, Qi Y-J, Xiang X-Y et al (2001) Time-dependent plasticity of synaptic transmission produced by long-term potentiation of C-fiber evoked field potentials in rat spinal dorsal horn. Neurosci Lett 315:81–84PubMedCrossRefGoogle Scholar
  66. Zhang X-C, Zhang Y-Q, Zhao Z-Q (2005) Involvement of nitric oxide in long-term potentiation of spinal nociceptive responses in rats. Neuroreport 16:1197–1201PubMedCrossRefGoogle Scholar
  67. Zhou L-J, Zhong Y, Ren W-J et al (2008) BDNF induces late-phase LTP of C-fiber evoked field potentials in rat spinal dorsal horn. Exp Neurol 212:507–514PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  1. 1.Department of NeurophysiologyCenter for Brain Research, Medical University of ViennaAustria

Personalised recommendations