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Table 2 Targets for prevention of LTP induction.

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]

[4, 7, 13, 17, 21, 42, 83, 101, 102, 134, 268, 274]

X [275]

 

NMDA-2B R

Ro 25-6981

antagonist

X

  

•

 

WDR neuron AP firing

[276, 277]

X [276]

mGluRs

mGluRI

AIDA, 4-CPG

antagonist

X

X

 

•

•

The mGluR1 antagonist LY367385 reduces long-lasting facilitation of presynaptic excitation [32] (optical imaging)

[38, 40]

X [278–280]

 

mGluRII, III

EGLU, LY341495, MSOP

antagonist

0

  

•

  

[40]

 

VGCC

T-type VDCC

mibefradil, Ni2+

antagonist

X

X

 

•

•

 

[4, 7, 17]

 
 

α2δ-subunit of VGCCs

gabapentin

 

0

  

•

  

[65]

0 [60, 62]

NK1R

NK1R

RP67580, 703,606

antagonist

X

X

 

•

•

 

[3, 4, 7, 17]

X [69, 281]

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

[6, 83]

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

•

  

[3, 4, 6, 7, 21] and others

 
  

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

  

•

  

[101, 102]

X [100, 102, 285, 286]

 

EphB R

ephrinB1-Fc

agonist

0

  

•

  

[101, 102]

 

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)

[4, 14]

X [14, 287, 288]

 

extracellular NO

PTIO, hemoglobin

scavenger

X

X

 

•

•

 

[4, 14]

X [289] (NMDA-induced hyperalgesia)

 

sGC

ODQ, MD

inhibitor

X

X

 

•

•

 

[4, 29]

 
 

mono-, poly ADPRT

nicotonamide, benzamide

inhibitor

0

  

•

  

[29]

 

Signal transduction pathways

CaMKII

KN-93, AIP, NK-62

inhibitor

X

X

0

•

•

 

[4, 7, 21, 143]

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

•

•

 

[4, 7, 21, 143]

X

 

PLC

U73122

inhibitor

X

X

 

•

•

 

[4, 7, 17]

X [293]

 

IP3R

2-APB

inhibitor

X

X

  

•

 

[4, 17]

 
 

RyR

Dantrolene, ryanodine

inhibitor

X

X

X

•

  

[7, 21, 108]

 
 

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]

X [296, 297]

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]

X [302, 303]

 

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]

  1. X, complete block or significant inhibition of LTP induction (left part of the table) or hyperalgesia induction (right part of the table)
  2. 0, no effect on LTP induction
  3. * Gives example of reports where spinal administration of drugs before induction of hyperalgesia prevented or significantly depressed or delayed the development of hyperalgesia in response to peripheral inflammation, nerve injury or LTP-inducing conditioning stimulation. Where other stimuli were used to induce hyperalgesia, this is indicated. For a more complete review of drugs influencing hyperalgesia and allodynia, see [2].