Table 2.

Targets for prevention of LTP induction.

	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]

X, complete block or significant inhibition of LTP induction (left part of the table) or hyperalgesia induction (right part of the table)

0, no effect on LTP induction

* 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].