Top

Published in:

Open Access 01-12-2007 | Review

Understanding LTP in pain pathways

Author: Jürgen Sandkühler

Published in: Molecular Pain | Issue 1/2007

Abstract

Long-term potentiation (LTP) at synapses of nociceptive nerve fibres is a proposed cellular mechanism underlying some forms of hyperalgesia. In this review fundamental properties of LTP in nociceptive pathways are described. The following topics are specifically addressed: A concise definition of LTP is given and a differentiation is made between LTP and "central sensitisation". How to (and how not to) measure and how to induce LTP in pain pathways is specified. The signal transduction pathways leading to LTP at C-fibre synapses are highlighted and means of how to pre-empt and how to reverse LTP are delineated. The potential functional roles of LTP are evaluated at the cellular level and at the behavioural level in experimental animals. Finally, the impact of LTP on the perception of pain in human subjects is discussed.

Available only for authorised users

Bliss TVP, Collingridge GL: A synaptic model of memory: long-term potentiation in the hippocampus. Nature 1993, 361: 31–39. 10.1038/361031a0PubMedCrossRef

Malenka RC, Bear MF: LTP and LTD: an embarrassment of riches. Neuron 2004, 44: 5–21. 10.1016/j.neuron.2004.09.012PubMedCrossRef

Bailey CH, Kandel ER, Si K: The persistence of long-term memory: a molecular approach to self-sustaining changes in learning-induced synaptic growth. Neuron 2004, 44: 49–57. 10.1016/j.neuron.2004.09.017PubMedCrossRef

Lisman J, Raghavachari S: A unified model of the presynaptic and postsynaptic changes during LTP at CA1 synapses. Sci STKE 2006, 2006: 1–15.CrossRef

Mantyh PW, Rogers SD, Honoré P, Allen BJ, Ghilardi JR, Li J, et al.: Inhibition of hyperalgesia by ablation of lamina I spinal neurons expressing the substance P receptor. Science 1997, 278: 275–279. 10.1126/science.278.5336.275PubMedCrossRef

Nichols ML, Allen BJ, Rogers SD, Ghilardi JR, Honoré P, Luger NM, et al.: Transmission of chronic nociception by spinal neurons expressing the substance P receptor. Science 1999, 286: 1558–1561. 10.1126/science.286.5444.1558PubMedCrossRef

Randic M, Jiang MC, Cerne R: Long-term potentiation and long-term depression of primary afferent neurotransmission in the rat spinal cord. J Neurosci 1993, 13: 5228–5241.PubMed

Ikeda H, Heinke B, Ruscheweyh R, Sandkühler J: Synaptic plasticity in spinal lamina I projection neurons that mediate hyperalgesia. Science 2003, 299: 1237–1240. 10.1126/science.1080659PubMedCrossRef

Liu XG, Sandkühler J: 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 1997, 78: 1973–1982.PubMed

10.

Schouenborg J: Functional and topographical properties of field potentials evoked in rat dorsal horn by cutaneous C-fibre stimulation. J Physiol 1984, 356: 169–192.PubMedCentralPubMedCrossRef

11.

Ikeda H, Murase K: Glial nitric oxide-mediated long-term presynaptic facilitation revealed by optical imaging in rat spinal dorsal horn. J Neurosci 2004, 24: 9888–9896. 10.1523/JNEUROSCI.2608-04.2004PubMedCrossRef

12.

Ikeda H, Stark J, Fischer H, Wagner M, Drdla R, Jäger T, et al.: Synaptic amplifier of inflammatory pain in the spinal dorsal horn. Science 2006, 312: 1659–1662. 10.1126/science.1127233PubMedCrossRef

13.

Liu XG, Sandkühler J: 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 1995, 191: 43–46. 10.1016/0304-3940(95)11553-0PubMedCrossRef

14.

Ma J-Y, Zhao Z-Q: The involvement of glia in long-term plasticity in the spinal dorsal horn of the rat. Neuroreport 2002, 13: 1781–1784. 10.1097/00001756-200210070-00017PubMedCrossRef

15.

Liu XG, Morton CR, Azkue JJ, Zimmermann M, Sandkühler J: Long-term depression of C-fibre-evoked spinal field potentials by stimulation of primary afferent Aδ-fibres in the adult rat. Eur J Neurosci 1998, 10: 3069–3075. 10.1046/j.1460-9568.1998.00310.xPubMedCrossRef

16.

Handwerker HO, Anton F, Reeh PW: Discharge patterns of afferent cutaneous nerve fibers from the rat's tail during prolonged noxious mechanical stimulation. Exp Brain Res 1987, 65: 493–504. 10.1007/BF00235972PubMedCrossRef

17.

Puig S, Sorkin LS: Formalin-evoked activity in identified primary afferent fibers: systemic lidocaine suppresses phase-2 activity. Pain 1996, 64: 345–355. 10.1016/0304-3959(95)00121-2PubMedCrossRef

18.

Wei F, Vadakkan KI, Toyoda H, Wu L-J, Zhao M-G, Xu H, et al.: Calcium calmodulin-stimulated adenylyl cyclases contribute to activation of extracellular signal-regulated kinase in spinal dorsal horn neurons in adult rats and mice. J Neurosci 2006, 26: 851–861. 10.1523/JNEUROSCI.3292-05.2006PubMedCrossRef

19.

Terman GW, Eastman CL, Chavkin C: Mu opiates inhibit long-term potentiation induction in the spinal cord slice. J Neurophysiol 2001, 85: 485–494.PubMed

20.

Lever IJ, Bradbury EJ, Cunningham JR, Adelson DW, Jones MG, McMahon SB, et al.: Brain-derived neurotrophic factor is released in the dorsal horn by distinctive patterns of afferent fiber stimulation. J Neurosci 2001, 21: 4469–4477.PubMed

21.

Hartmann B, Ahmadi S, Heppenstall PA, Lewin GR, Schott C, Borchardt T, et al.: The AMPA receptor subunits GluR-A and GluR-B reciprocally modulate spinal synaptic plasticity and inflammatory pain. Neuron 2004, 44: 637–650. 10.1016/j.neuron.2004.10.029PubMedCrossRef

22.

Sandkühler J, Liu X: Induction of long-term potentiation at spinal synapses by noxious stimulation or nerve injury. Eur J Neurosci 1998, 10: 2476–2480. 10.1046/j.1460-9568.1998.00278.xPubMedCrossRef

23.

Yang H-W, Zhou L-J, Hu N-W, Xin W-J, Liu X-G: Activation of spinal D1/D5 receptors induces latep hase LTP of c-fiber evoked field potentials in rat spinal dorsal horn. J Neurophysiol 2005, 94: 961–967. 10.1152/jn.01324.2004PubMedCrossRef

24.

Liu XG, Sandkühler J: Activation of spinal N -methyl-D-aspartate or neurokinin receptors induces long-term potentiation of spinal C-fibre-evoked potentials. Neuroscience 1998, 86: 1209–1216. 10.1016/S0306-4522(98)00107-9PubMedCrossRef

25.

Miletic G, Miletic V: Contribution of GABA-A receptors to metaplasticity in the spinal dorsal horn. Pain 2001, 90: 157–162. 10.1016/S0304-3959(00)00398-5PubMedCrossRef

26.

Miletic G, Miletic V: Long-term changes in sciatic-evoked A-fiber dorsal horn field potentials accompany loose ligation of the sciatic nerve in rats. Pain 2000, 84: 353–359. 10.1016/S0304-3959(99)00227-4PubMedCrossRef

27.

Miletic G, Draganic P, Pankratz MT, Miletic V: 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 2003, 105: 347–353. 10.1016/S0304-3959(03)00250-1PubMedCrossRef

28.

Mellor J, Nicoll RA, Schmitz D: Mediation of hippocampal mossy fiber long-term potentiation by presynaptic I _h channels. Science 2002, 295: 143–147. 10.1126/science.1064285PubMedCrossRef

29.

Nicoll RA: Expression mechanisms underlying long-term potentiation: a postsynaptic view. Philos Trans R Soc Lond B Biol Sci 2003, 358: 721–726. 10.1098/rstb.2002.1228PubMedCentralPubMedCrossRef

30.

Malinow R: AMPA receptor trafficking and long-term potentiation. Philos Trans R Soc Lond B Biol Sci 2003, 358: 707–714. 10.1098/rstb.2002.1233PubMedCentralPubMedCrossRef

31.

Azkue JJ, Liu XG, Zimmermann M, Sandkühler J: 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 2003, 106: 373–379. 10.1016/j.pain.2003.08.007PubMedCrossRef

32.

Lieberman DN, Mody I: Substance P enhances NMDA channel function in hippocampal dentate gyrus granule cells. J Neurophysiol 1998, 80: 113–119. 10.1159/000014965PubMed

33.

Tong C-K, MacDermott AB: Both Ca²⁺ -permeable and – impermeable AMPA receptors contribute to primary synaptic drive onto rat dorsal horn neurons. J Physiol 2006, 575: 133–144. 10.1113/jphysiol.2006.110072PubMedCentralPubMedCrossRef

34.

Zhang X-C, Zhang Y-Q, Zhao Z-Q: Involvement of nitric oxide in long-term potentiation of spinal nociceptive responses in rats. Neuroreport 2005, 16: 1197–1201. 10.1097/00001756-200508010-00013PubMedCrossRef

35.

Xin W-J, Gong Q-J, Xu J-T, Yang H-W, Zang Y, Zhang T, et al.: 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 2006, 84: 934–943. 10.1002/jnr.21013PubMedCrossRef

36.

Yang H-W, Hu X-D, Zhang H-M, Xin W-J, Li M-T, Zhang T, et al.: 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 2004, 91: 1122–1133. 10.1152/jn.00735.2003PubMedCrossRef

37.

Hu N-W, Zhang H-M, Hu X-D, Li M-T, Zhang T, Zhou L-J, et al.: Protein synthesis inhibition blocks the late-phase LTP of C-fiber evoked field potentials in rat spinal dorsal horn. J Neurophysiol 2003, 89: 2354–2359. 10.1152/jn.01027.2002PubMedCrossRef

38.

Sandkühler J: Learning and memory in pain pathways. Pain 2000, 88: 113–118. 10.1016/S0304-3959(00)00424-3PubMedCrossRef

39.

Willis WD: Role of neurotransmitters in sensitization of pain responses. Ann N Y Acad Sci 2001, 933: 142–156.PubMedCrossRef

40.

Meller ST, Gebhart GF: Nitric oxide (NO) and nociceptive processing in the spinal cord. Pain 1993, 52: 127–136. 10.1016/0304-3959(93)90124-8PubMedCrossRef

41.

Petersen-Zeitz KR, Basbaum AI: Second messengers, the substantia gelatinosa and injury-induced persistent pain. Pain 1999, (Suppl 6):S5–12. 10.1016/S0304-3959(99)00132-3

42.

Benrath J, Brechtel C, Martin E, Sandkühler J: Low doses of fentanyl block central sensitization in the rat spinal cord in vivo . Anesthesiology 2004, 100: 1545–1551. 10.1097/00000542-200406000-00030PubMedCrossRef

43.

Ge Y-X, Xin W-J, Hu N-W, Zhang T, Xu J-T, Liu X-G: Clonidine depresses LTP of C-fiber evoked field potentials in spinal dorsal horn via NO-cGMP pathway. Brain Res 2006, 1118: 58–65. 10.1016/j.brainres.2006.08.009PubMedCrossRef

44.

Hu X-D, Ge Y-X, Hu N-W, Zhang H-M, Zhou L-J, Zhang T, et al.: Diazepam inhibits the induction and maintenance of LTP of C-fiber evoked field potentials in spinal dorsal horn of rats. Neuropharmacology 2006, 50: 238–244. 10.1016/j.neuropharm.2005.09.010PubMedCrossRef

45.

Zhang H-M, Qi Y-J, Xiang X-Y, Zhang T, Liu X-G: Time-dependent plasticity of synaptic transmission produced by long-term potentiation of C-fiber evoked field potentials in rat spinal dorsal horn. Neurosci Lett 2001, 315: 81–84. 10.1016/S0304-3940(01)02343-6PubMedCrossRef

46.

Afrah AW, Fiskå A, Gjerstad J, Gustafsson H, Tjølsen A, Olgart L, et al.: Spinal substance P release in vivo during the induction of long-term potentiation in dorsal horn neurons. Pain 2002, 96: 49–55. 10.1016/S0304-3959(01)00414-6PubMedCrossRef

47.

Rygh LJ, Suzuki R, Rahman W, Wong Y, Vonsy JL, Sandhu H, et al.: Local and descending circuits regulate long-term potentiation and zif268 expression in spinal neurons. Eur J Neurosci 2006, 24: 761–772. 10.1111/j.1460-9568.2006.04968.xPubMedCrossRef

48.

Vikman KS, Duggan AW, Siddall PJ: Increased ability to induce long-term potentiation of spinal dorsal horn neurones in monoarthritic rats. Brain Res 2003, 990: 51–57. 10.1016/S0006-8993(03)03385-7PubMedCrossRef

49.

Coull JAM, Boudreau D, Bachand K, Prescott SA, Nault F, Sik A, et al.: Trans-synaptic shift in anion gradient in spinal lamina I neurons as a mechanism of neuropathic pain. Nature 2003, 424: 938–942. 10.1038/nature01868PubMedCrossRef

50.

Coull JAM, Beggs S, Boudreau D, Boivin D, Tsuda M, Inoue K, et al.: BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain. Nature 2005, 438: 1017–1021. 10.1038/nature04223PubMedCrossRef

51.

Klein T, Magerl W, Hopf H-C, Sandkühler J, Treede R-D: Perceptual correlates of nociceptive long-term potentiation and long-term depression in humans. J Neurosci 2004, 24: 964–971. 10.1523/JNEUROSCI.1222-03.2004PubMedCrossRef

52.

Klein T, Magerl W, Nickel U, Hopf H-C, Sandkühler J, Treede R-D: Effects of the NMDA-receptor antagonist ketamine on perceptual correlates of long-term potentiation within the nociceptive system. Neuropharmacology 2006, 52: 655–661. 10.1016/j.neuropharm.2006.09.008PubMedCrossRef

53.

Lang S, Klein T, Magerl W, Treede R-D: Modality-specific sensory changes in humans after the induction of long-term potentiation (LTP) in cutaneous nociceptive pathways. Pain 2007, 128: 254–263. 10.1016/j.pain.2006.09.026PubMedCrossRef

54.

Hansen N, Klein T, Magerl W, Treede R-D: Psychophysical evidence for long-term potentiation of C-fiber and Aδ-fiber pathways in humans by analysis of pain descriptors. J Neurophysiol 2007, 97: 2559–2563. 10.1152/jn.01125.2006PubMedCrossRef

55.

Lee H-K, Takamiya K, Han J-S, Man H, Kim C-H, Rumbaugh G, et al.: Phosphorylation of the AMPA receptor GluR1 subunit is required for synaptic plasticity and retention of spatial memory. Cell 2003, 112: 631–643. 10.1016/S0092-8674(03)00122-3PubMedCrossRef

56.

Boehm J, Kang M-G, Johnson RC, Esteban J, Huganir RL, Malinow R: Synaptic Incorporation of AMPA Receptors during LTP Is Controlled by a PKC Phosphorylation Site on GluR1. Neuron 2006, 51: 213–225. 10.1016/j.neuron.2006.06.013PubMedCrossRef

Title: Understanding LTP in pain pathways
Author: Jürgen Sandkühler
Publication date: 01-12-2007
Publisher: BioMed Central
Published in: Molecular Pain / Issue 1/2007
Electronic ISSN: 1744-8069
DOI: https://doi.org/10.1186/1744-8069-3-9

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Understanding LTP in pain pathways

Abstract

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 1/2007

Do motor control genes contribute to interindividual variability in decreased movement in patients with pain?

Morphine reduces local cytokine expression and neutrophil infiltration after incision

Activation of the neurokinin-1 receptor by substance P triggers the release of substance P from cultured adult rat dorsal root ganglion neurons

Comparison of evoked vs. spontaneous tics in a patient with trigeminal neuralgia (tic doloureux)

Techniques for assessing knee joint pain in arthritis

Mechanically-evoked C-fiber activity in painful alcohol and AIDS therapy neuropathy in the rat