From: Long-term potentiation in spinal nociceptive pathways as a novel target for pain therapy
 | Target | Substance | Action at target | HFS | LFS | Opioid with- drawal | in vivo | in vitro | Comments | References | Effect of equivalent drugs on hyperalgesia induction* |
---|---|---|---|---|---|---|---|---|---|---|---|
AMPAR | AMPAR | NBQX | antagonist | X |  |  | • |  | WDR neuron AP firing | [30] | X [273] |
NMDAR | NMDAR | AP5, D-AP5, MK 801, ketamine | antagonist | X | X | X | • | • | NMDAR antagonists also prevent LTP induced by nerve transsection [11], BDNF [140] and LTP of human pain perception [20] | X [275] | |
 | NMDA-2B R | Ro 25-6981 | antagonist | X |  |  | • |  | WDR neuron AP firing | X [276] | |
mGluRs | mGluRI | AIDA, 4-CPG | antagonist | X | X |  | • | • | The mGluR1 antagonist LY367385 reduces long-lasting facilitation of presynaptic excitation [32] (optical imaging) | ||
 | mGluRII, III | EGLU, LY341495, MSOP | antagonist | 0 |  |  | • |  |  | [40] |  |
VGCC | T-type VDCC | mibefradil, Ni2+ | antagonist | X | X |  | • | • |  |  | |
 | α2δ-subunit of VGCCs | gabapentin |  | 0 |  |  | • |  |  | [65] | |
NK1R | NK1R | RP67580, 703,606 | antagonist | X | X |  | • | • |  | ||
GABAAR | GABAAR | diazepam | Current amplifier | X |  |  | • |  |  | [70] |  |
Opioid receptors | μ-opioid receptors | fentanyl, DAMGO | agonist | X | X |  | • | • | Drugs depress baseline responses. Fentanyl prevents LTP at low but not high doses | X [282] | |
Descending inhibition | α2- adrenergic receptors | clonidine | agonist | X |  |  | • |  |  | [90] | X [283] (human capsicin model) |
 | 5-HT3 receptor | odansetron | antagonist | X |  |  | • |  | WDR neuron AP firing | [31] |  |
 | D1/D5 dopamine receptor | SCH 23390 | antagonist | 0 |  |  | • |  | Selectively blocks L-LTP but not E-LTP | [91] |  |
Anaesthetic gases |  | isoflurane, sevoflurane, urethane |  | 0 | 0 | 0 | • |  |  |  | |
 |  | Xenon |  | X |  |  | • |  |  | [92] |  |
Neurotrophins | TrkB receptor | K252a, TrkB- Fc | Trk inhibitor, BNDF scavenger | 0 | 0 |  | • |  | Blocks L-LTP after LFS | [140] | X [284] |
EphR-ephrin signalling | EphB R | EphB1-Fc EphB2-Fc | antagonist | X |  |  | • |  |  | ||
 | EphB R | ephrinB1-Fc | agonist | 0 |  |  | • |  |  |  | |
NO-pathway | NOS | L-NMMA, L-NAME | inhibitor | X | X |  | • | • | [14, 29]: deep dorsal horn. Induction of long-lasting facilitation of presynaptic electrical activity by LFS is reduced by blockers of nNOS and iNOS [32] (optical imaging) | ||
 | extracellular NO | PTIO, hemoglobin | scavenger | X | X |  | • | • |  | X [289] (NMDA-induced hyperalgesia) | |
 | sGC | ODQ, MD | inhibitor | X | X |  | • | • |  |  | |
 | mono-, poly ADPRT | nicotonamide, benzamide | inhibitor | 0 |  |  | • |  |  | [29] |  |
Signal transduction pathways | CaMKII | KN-93, AIP, NK-62 | inhibitor | X | X | 0 | • | • |  | X [290] | |
 | PKA | Rp-CPT-cAMPS | inhibitor | X |  |  | • |  |  | [143] | X [291, 292] (hyperalgesia induced by i.th. CGRP/subcutaneous bee venom injury) |
 | PKC | Chelerythrine, Gö 6983, GF109203X | inhibitor | X | X | X | • | • |  | X | |
 | PLC | U73122 | inhibitor | X | X |  | • | • |  | X [293] | |
 | IP3R | 2-APB | inhibitor | X | X |  |  | • |  |  | |
 | RyR | Dantrolene, ryanodine | inhibitor | X | X | X | • |  |  |  | |
 | ERK | PD98059 | inhibitor | X |  |  | • |  |  | [110] | X [294] |
 | JNK | SP600125 | inhibitor | 0 |  |  | • |  | Same drugs prevent induction of LTP by TNF-α in neuropathic rats | [111] | X [295] |
 | p38 MAPK | SB203580 | inhibitor | 0 |  |  | • |  |  | [111] | |
Glial cells/neuroimmune mechanisms | Glial metabolism | fluorocitrate | inhibitor | X |  |  | • |  | Deep dorsal horn. Under fluorocitrate, HFS induces LTD. Also blocks induction of long-lasting potentiation of presynaptic electrical activity by LFS [32] (optical imaging) | [114] | X [298] |
 | Microglia metabolism | minocycline | inhibitor | X |  |  | • |  | Under minocycline, HFS induces LTD | [113] | X [299] |
 | Microglia SKF (Src-family kinases) | PP2, SU6656 | inhibitor | X |  |  | • |  | HFS activates SFKs selectivey in microglia. Under SKF inhibitors, HFS induces LTD | [113] | X [124] |
 | GLT-1 | DHK | inhibitor | X |  |  | • |  | Deep dorsal horn | [128] | X [300] |
 | TNF α receptor | TNF-α | agonist |  | 0 |  | • |  |  | [111] | X [301] |
 | TNF-α | TNF-α antibody | inhibitor |  |  |  |  | • | Optical imaging | [123] | |
 | IL-6 | IL-6 antibody | inhibitor |  |  |  |  | • | after bulk loading of voltage-sensitive dye; LTP induced by αβmeATP X | [123] | X [304] mechanical hyperalgesia induced by fractalkine injection; [297] |