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Review
. 2012 Feb;12(1):18-27.
doi: 10.1016/j.coph.2011.10.018. Epub 2011 Nov 9.

Hyperalgesia by synaptic long-term potentiation (LTP): an update

Jürgen Sandkühler  1 , Doris Gruber-Schoffnegger
Affiliations
Review

Hyperalgesia by synaptic long-term potentiation (LTP): an update

Jürgen Sandkühler et al. Curr Opin Pharmacol. 2012 Feb.

Abstract

Long-term potentiation of synaptic strength (LTP) in nociceptive pathways shares principle features with hyperalgesia including induction protocols, pharmacological profile, neuronal and glial cell types involved and means for prevention. LTP at synapses of nociceptive nerve fibres constitutes a contemporary cellular model for pain amplification following trauma, inflammation, nerve injury or withdrawal from opioids. It provides a novel target for pain therapy. This review summarizes recent progress which has been made in unravelling the properties and functions of LTP in the nociceptive system and in identifying means for its prevention and reversal.

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Figures

Figure 1
Figure 1
Induction of LTP at C-fibre synapses. The figure illustrates different activity-dependent and -independent forms of LTP at C-fibre synapses. The graphs display mean time courses of amplitudes of C-fibre-evoked field potentials measured in the superficial spinal dorsal horn of adult, deeply anaesthetized rats. Field potentials were evoked by stimulation of sciatic nerve fibres at C-fibre intensity. Conditioning stimulation consisted of electrical stimulation of sciatic nerve fibre afferents at a high frequency (A, HFS, 100 Hz given four times for 1 s at 10 s intervals), at a low frequency (B, LFS, 2 Hz for 2 min), or subcutaneous injection of transient receptor potential vanilloid 1 channel agonist capscaicin (C, 1%, 100 μl). In D LTP was induced upon withdrawal from a brief (1 h) intravenous application of a high dose of remifentanil (450 mg kg−1 h−1 for 1 h, black horizontal bar). Modified from [15,18••].
Figure 2
Figure 2
Signalling pathways of LTP induction at C-fibre synapses. The schemes summarize elements of the signalling pathways which are required (A) or sufficient (B) for the induction of LTP at spinal C-fibre synapses. The elements involved in LTP induction are typically identified by the respective blockers (required elements) or activators (sufficient elements) which were applied topically to the spinal cord. Many of the involved signalling elements are expressed at more than one cellular site as shown in the figure. The cellular site(s) of action is/are thus in most cases not known, except when substances were applied directly into the postsynaptic neuron as shown for Ca2+, NMDAR, and GPCR (which are in boxes here) in A. Suggested signalling pathways are indicated by arrows. Diffusion of elements is illustrated by dotted lines. * indicates that activation of this element induces LTP in spinalised animals only. Abbreviations and literature: AMPAR: α-amino-3-3hydroxy-5-5methyl-4-4isoxazoleproprionic acid receptor [72]; ATP: Adenosine triphosphate [22•,27]; BDNF: Brain derived neurotrophic factor [20,34]; CaMKII: calcium/calmodulin-dependent protein kinase II [15,18••,19,73]; D1,5R: Dopamine receptor D1,5 [74]; EphB: Ephrin B receptor [29,75•]; ERK: Extracellular signal-regulated kinase [76]; GLT-1: Glutamate transporter 1 [77]; GPCR: G-protein coupled receptor [18••]; IP3R: Inositol triphosphate receptor [14,15]; mGluR1: Metabotropic glutamate receptor group 1 [78,79]; NK1R: Neurokinin 1 receptor [14,15,19,80,81]; NK2R: Neurokinin 2 receptor [80,81]; NMDAR: N-methyl d-aspartate receptor [11,14–16,18••,19,81]; NO: Nitric oxide [15,65]; NOS: Nitric oxide synthase [15,65]; PKA: Protein kinase A [73]; PKC: Protein kinase C [15,18••,19,73]; PLC: Phospholipase C [14,15,19]; P2X7, P2X4: Ionotropic purinergic receptor [22•,27]; p38MAPK: p38 mitogen-activated protein kinases [20,27]; ROS: Reactive oxygen species [24•]; RyR: Ryanodine receptor [18••,19,21]; SFK: Src family kinases [25]; TNFα: Tumour necrosis factor α [25,32]; TNFαR: Tumour necrosis factor α receptor [25,32]; TrkBR: Neurotrophic tyrosine kinase receptor type 2 [20]; T-type VGCC: T-type voltage gated calcium channel [14,15,19]; 5HT3R: Serotonin type 3 receptor [82].
Figure 3
Figure 3
Signalling pathways of LTP maintenance and LTP reversal at C-fibre synapses. The schemes summarize elements of signalling pathways which are required for the maintenance of LTP at spinal C-fibre synapses. Thus, when any of these elements is blocked established LTP diminishes or disappears (required elements for LTP maintenance, A). The diagram in B summarizes elements which, when activated reverse established LTP. These sufficient elements for the reversal of LTP are underlined. Elements which are not underlined are required for the reversal of LTP. When blocked these elements prevent the reversal of LTP by at least one of the sufficient elements. Blockers and activators of the respective elements were usually applied topically to the spinal cord. Many of the known signalling elements are expressed at more than one cellular site as shown in the figure. The cellular site(s) of action is/are thus not known in most cases. Suggested signalling pathways are indicated by arrows. Diffusion of elements is illustrated by dotted lines. Abbreviations and literature: AMPAR: α-amino-3-3hydroxy-5-5methyl-4-4isoxazoleproprionic acid receptor (unpubl.); A1R: Adenosine 1 receptor [83]; α2-AR: α2-adrenergic receptor [84]; α2δ VGCC: Voltage gated calcium channel [85]; CaMKII: Calcium/calmodulin-dependent protein kinase II [73]; cGMP: Cyclic guanosine monophosphate [84]; D1,5R: Dopamine receptor D1,5 [74]; ERK: Extracellular signal-regulated kinase [76,86]; GABAAR: γ-aminobutyric acid A receptor [57]; mAChR: Muscarinic acetylcholine receptor [84]; mGluR1: Metabotropic glutamate receptor group 1 (unpubl.); MOR: μ-opioid-receptor [85]; NMDAR: N-methyl d-aspartate receptor (unpubl.); NO: Nitric oxide [84]; NOS: Nitric oxide synthase [84] PKA: Protein kinase A [73]; PKC: Protein kinase [73]; PP1: Protein phosphatase 1 (unpubl.); RyR: Ryanodine receptor (unpubl.); TrkBR: Neurotrophic tyrosine kinase receptor type 2 [34].
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