Induction of long-term potentiation of single wide dynamic range neurones in the dorsal horn is inhibited by descending pathways

Previous studies have shown that long-term potentiation (LTP) in the dorsal horn may be induced by noxious stimuli. In this study it is investigated whether induction of LTP in the dorsal horn may be affected by the descending pathways. Extracellular recordings of wide dynamic range (WDR) neurones in the lumbar dorsal horn in intact urethane-anaesthetized Sprague--Dawley rats were performed, and the electrically evoked neuronal responses in these neurones were defined as A-fibre and C-fibre responses according to latencies. Using a short-term cold block of the thoracic spinal cord, which produced a completely reversible increase of the A-fibre and C-fibre responses, the influence of the descending inhibitory system on the induction of LTP by electrical high-frequency conditioning applied to the sciatic nerve was examined. As previously shown the A-fibre responses were almost unchanged following the conditioning. In contrast, the C-fibre responses following the same conditioning were strongly increased. Thus, a clear LTP of the nociceptive transmission in the dorsal horn was observed following electrical high-frequency conditioning. Interestingly, we found that the LTP was more powerful when the effects of the descending pathways were temporarily eliminated during conditioning. It is concluded that induction of LTP by electrical high-frequency conditioning stimulation, which may be part of the wider term central sensitization, is inhibited by descending pathways.     

Natural noxious stimulation can induce long-term increase of spinal nociceptive responses.

It is conceivable that plasticity in pain control systems and chronic pain may be due to mechanisms similar to learning. Long-term potentiation (LTP) in the hippocampus is often studied as a model of learning and memory. It has recently been shown that long-term excitation may be induced in single wide dynamic range (WDR) neurones in the spinal dorsal horn of rats after tetanic stimulation to the sciatic nerve. The present study shows that similar long-term changes can also be induced by a severe natural stimulus. Single unit extracellular recordings were made in urethane anaesthetized rats and the firing responses of WDR neurones evoked by a single electrical stimulus to the peripheral nerve were recorded every 4 min. After repeated crushing of tissue (including bone) corresponding to the receptive field of the WDR neurones (the conditioning stimulus) followed by a proximal total peripheral nerve block, the C-fibre evoked responses were increased (P < 0.001) for a 3 h observation period compared with baseline responses and control animals. In control animals the nerve block was applied before the conditioning stimulus. We suggest that a long-term increase of the excitability of WDR neurones may be important for the development of long lasting and chronic pain disorders after an acute but severe noxious stimulus.     

Paraventricular oxytocinergic hypothalamic prevention or interruption of long-term potentiation in dorsal horn nociceptive neurons: Electrophysiological and behavioral evidence

Spinal long-term potentiation (LTP) elicited by noxious stimulation enhances the responsiveness of dorsal horn nociceptive neurons to their normal input, and may represent a key mechanism of central sensitization by which acute pain could turn into a chronic pain state. This study investigated the electrophysiological and behavioral consequences of the interactions between LTP and descending oxytocinergic antinociceptive mechanisms mediated by the hypothalamic paraventricular nucleus (PVN). PVN stimulation or intrathecal oxytocin (OT) reduced or prevented the ability of spinal LTP to facilitate selectively nociceptive-evoked responses of spinal wide dynamic range (WDR) neurons recorded in anesthetized rats. In a behavioral model developed to study the effects of spinal LTP on mechanical withdrawal thresholds in freely moving rats, the long-lasting LTP-mediated mechanical hyperalgesia was transiently interrupted or prevented by either PVN stimulation or intrathecal OT. LTP mediates long-lasting pain hypersensitivity that is strongly modulated by endogenous hypothalamic oxytocinergic descending controls.     

Role of voltage-dependent calcium channel subtypes in spinal long-term potentiation of C-fiber-evoked field potentials

Activity-dependent increases in the responsiveness of spinal neurons to their normal afferent input, termed central sensitization, have been suggested to play a key role in abnormal pain sensation. We investigated the role of distinct voltage-dependent calcium channel (VDCC) subtypes in the long-term potentiation (LTP) of C-fiber-evoked field potentials (FPs) recorded in the spinal dorsal horn of rats, that is, a synaptic model to describe central sensitization. When spinally applied, we observed that omega-conotoxin GVIA (ω-CgTx), an N-type VDCC antagonist, produced a dose-dependent and prolonged inhibition of basal C-fiber-evoked FPs in naïve animals. ω-CgTx did not perturb the induction of LTP by high-frequency stimulation (HFS) of the sciatic nerve; however, potentiation was maintained at a lower level. Following the establishment of spinal LTP in naïve animals, the inhibitory effect of ω-CgTx on C-fiber-evoked FPs was significantly increased. Furthermore, in animals with chronic pain produced via peripheral nerve injury, where spinal LTP was barely induced by HFS, basal C-fiber-evoked FPs were strongly inhibited by ω-CgTx. As a result, ω-CgTx exerted a similar inhibitory profile on C-fiber-evoked FPs following the establishment of spinal LTP and chronic pain. In contrast, spinally administered omega-agatoxin IVA (ω-Aga-IVA), a P/Q-type VDCC antagonist, showed little effect on C-fiber-evoked FPs either before or after the establishment of LTP, but strongly suppressed LTP induction. These results demonstrate the requirement of N- and P/Q-type VDCCs in the maintenance and induction of LTP in the spinal dorsal horn, respectively, and their distinct contribution to nociceptive synaptic transmission and its plasticity.     

电刺激红核对WDR神经元C反应的抑制作用

目的：分析红核的抗伤害作用和有关机制。方法：用玻璃微电极细胞外记录大鼠脊髓背角广动力型神经元(wide dynamic：range，WDR)的单位放电，观察电刺激红核对WDR神经元伤害性反应（C-反应)的影响。结果：电刺激红核对WDR神经元C-反应具有抑制作用。电刺激红核对同侧WDR神经元C-反应的抑制作用弱于对侧。静注纳洛酮对电刺激红核的抑制作用无明显的影响。结论：红核参与伤害信息的处理，阿片机制似不参与上述作用。     

Spinal cord stimulation attenuates dorsal horn neuronal hyperexcitability in a rat model of mononeuropathy

The mechanisms underlying the relief of neuropathic pain of peripheral origin by spinal cord stimulation (SCS) are poorly understood. The present study was designed to investigate the effects of SCS on evoked and spontaneous discharges in dorsal horn neurons in intact and in nerve-injured rats subjected to partial sciatic nerve ligation according to Seltzer et al. (1990). Tactile sensitivity in the hind paw was assessed in behavioral tests using von Frey filaments. The presence of 'allodynia' was defined as a withdrawal response to a filament of 10 g or less. Under halothane/oxygen anesthesia the effects of SCS (50 Hz, 0.2 ms, 80-620 microA, 5 min.) on mechanically evoked (brush and innocuous press on the hind paw) responses and spontaneous discharges were investigated in wide-dynamic range (WDR) neurons in three groups of animals: (1) rats that displayed 'allodynia' after nerve ligation (2) rats without signs of 'allodynia' after surgery and (3) control, intact rats. A significantly increased frequency of spontaneous discharge and of responsiveness to brush and press was found in the group of allodynic, as compared with non-allodynic and control rats. The majority (63%) of the investigated neurons in these animals displayed afterdischarge in response to press stimulation. SCS induced a significant depression of both the principal response and the afterdischarge in allodynic rats: the discharge during brush stimulation was reduced to 86 +/- 8.2% and during press to 77.4 +/- 4.5% as compared with the prestimulation value. These depressive effects on evoked responses in allodynic rats outlasted SCS by 10.5 +/- 1.7 min during which time the responses gradually recovered. The frequency of spontaneous discharge was markedly decreased in approximately one third of the neurons, whereas in another third it was increased. In non-allodynic and control rats, SCS had no significant depressive effects on the evoked responses and spontaneous discharge. The results suggest that SCS may provide a suppressive action on dorsal horn neuronal hyperexcitability associated with signs of peripheral neuropathy. The suppressive effect of SCS on tactile allodynia, as previously observed in behavioral experiments, presumably corresponds to a normalization of the excitability of WDR cells in response to innocuous stimuli.     

Dorsal horn NK1-expressing neurons control windup of downstream trigeminal nociceptive neurons

Windup is a progressive, frequency-dependent increase in the excitability of trigeminal and spinal dorsal horn wide dynamic range (WDR) nociceptive neurons to repetitive stimulation of primary afferent nociceptive C-fibers. Superficial dorsal horn neurokinin 1 receptor (NK1R)-expressing neurons were recently shown to regulate sensitization of WDR nociceptive neurons through activation of a defined spino-bulbo-spinal loop. However, the windup of WDR nociceptive neurons was not regulated through this loop. In the present study, we sought to identify the alternative circuit activated by dorsal horn NK1Rs that mediates WDR neuron windup. As a model we used the rat spinal trigeminal nucleus, in which the subnucleus oralis (Sp5O) contains a pool of WDR neurons that receive their nociceptive C-input indirectly via interneurons located in the medullary dorsal horn (MDH). First, we found that intravenous injection of NK1R antagonists (SR140333 and RP67580) produced a reversible inhibition of Sp5O WDR neuron windup. Second, we anatomically identified in the MDH lamina III a subpopulation of NK1R-expressing local interneurons that relay nociceptive information from the MDH to downstream Sp5O neurons. Third, using microinjections of NK1R antagonists during in vivo electrophysiological recordings from Sp5O WDR neurons, we showed that WDR neuron windup depends on activation of NK1Rs located in the MDH laminae I-III. We conclude that, in contrast to central sensitization that is controlled by a spino-bulbo-spinal loop, Sp5O WDR neuron windup is regulated through a local circuit activated by MDH lamina III NK1Rs.     

Dorsal horn NMDA receptor function is changed after peripheral inflammation

The N-methyl-D-aspartic acid (NMDA) receptor antagonist D, L-2-amino-5-phosphonopentanoic acid (AP5) caused a stronger inhibition of wind-up in single wide dynamic range (WDR) neurons after carrageenan inflammation compared with control neurons without inflammation in the receptive field. This indicates that even a short period (2.5 h) of inflammation induces changes in the function of NMDA receptors. The drug effect was also studied in separate control experiments with few wind-up inducing stimulus trains and little nociceptive input prior to baseline recordings. In these control experiments all evoked responses were reduced by the drug, but the wind-up was significantly increased. A wind-up increase after NMDA receptor antagonism has been reported in two previous studies. Thus, other mechanisms than NMDA receptor stimulation may be more important for the wind-up in not sensitized dorsal horn neurons. As for long-term potentiation, it seems that NMDA receptor antagonists have an increased effect after sensitization. Thus, sensitized and not sensitized dorsal horn neurons may respond differently to an NMDA receptor active drug. In rats nerve stimulation and halothane anaesthesia induced larger evoked responses to afferent stimulation than cutaneous stimulation and urethane anaesthesia, the AP5 effect was however similar.     

Behavioural effects of LTP-inducing sciatic nerve stimulation in the rat

A short-lasting tetanic sciatic nerve stimulation that previously has been shown to be nociceptive only during the stimulation, induces long-term potentiation (LTP) of nociceptive evoked responses in wide dynamic range neurons in the dorsal horn of rats. The LTP may contribute to the process of central sensitization. We have shown that the tetanic conditioning stimulation with muscular contractions induces LTP of both Aβ- and C-fibre evoked responses. However, the same stimulation during muscular paralysis induces LTP only of C-fibre evoked responses. In the present study, we investigated the effects of this conditioning stimulation with or without muscular paralysis in behavioural tests in rats. Conditioning stimulation with muscular contractions caused a significant reduction of weight borne on the stimulated side, suggesting muscular soreness and peripheral sensitization. Conditioning stimulation during neuromuscular paralysis, which only has given LTP of C-fibre evoked responses in intact animals, caused no change in the weight borne on the stimulated side, suggesting less or even absence of allodynia. However, in these animals the response temperature in the hot plate test was increased both on the stimulated and on the contralateral side compared to sham-operated rats. In view of our recent results indicating that a descending inhibition reduces the expression of LTP in dorsal horn cells, and the suggestion by others that long-term descending inhibition may override a segmental facilitation, it is suggested that an increased long-lasting endogenous nociceptive inhibition is induced after LTP-inducing stimulation. This is an interesting parallel to stimulation-induced analgesia in humans. C 1999 European Federation of Chapters of the International Association for the Study of Pain     

Role of the NKCC1 co-transporter in sensitization of spinal nociceptive neurons

The Na⁺, K⁺, 2Cl⁻ co-transporter type 1 (NKCC1) plays a pivotal role in hyperalgesia associated with inflammatory stimuli. NKCC1 contributes to maintain high [Cl⁻]_i in dorsal root ganglia (DRG) neurons which cause primary afferent depolarization (PAD) when GABA_A receptors are activated. Enhanced GABA-induced depolarization, through increased NKCC1 activity, has been hypothesized to produce orthodromic spike activity of sufficient intensity to account for touch-induced pain. In the present study, we investigate this hypothesis using in vivo electrophysiology on rat dorsal horn neurons; the effects of spinal blockade of NKCC1 on intraplantar capsaicin-induced sensitization of dorsal horn neurons were examined. Single wide dynamic range (WDR) and nociceptive specific (NS) neuron activity in the dorsal horn was recorded using glass microelectrodes in anesthetized rats. Dorsal horn neurons with a receptive field on the plantar surface of the hindpaw were studied. Neuronal responses to mechanical stimuli (brush, von Frey filaments) were recorded ten minutes before intraplantar injection of 0.3 ml 0.1% capsaicin (CAP), 40 min after CAP and 15 min after local application of the NKCC1 blocker bumetanide (BTD; 500 μM) on the spinal cord. After CAP, low and high threshold stimulation of the cutaneous receptive field produced a significant enhancement in spike frequency over pre-CAP values in both WDR and NS neurons. Spinal BTD application reduced the spike frequency to baseline levels as well as attenuated the CAP-induced increases in background activity. Our data support the hypothesis that NKCC1 plays an important role in the sensitization of dorsal horn neurons following a peripheral inflammatory insult.     

Dorsal column-thalamic pathway is involved in thalamic hyperexcitability following peripheral nerve injury: a lesion study in rats with experimental mononeuropathy

A total of 68 neurons were recorded from the ventro-postero-lateral nucleus of thalamus (VPL) in rats with a unilateral chronic constriction injury (CCI) of the sciatic nerve (n=20), sham operation (n=24) and naive rats (n=24), and effects of the lesion of dorsal column (DC) pathway [DC lesion or DC+gracile nucleus lesions] on VPL nucleus neuronal activities were studied. In the VPL nucleus contralateral to the CCI (receiving input from the injured nerve), response latencies of low threshold mechanoreceptive (LTM) and wide dynamic range (WDR) neurons to electrical stimulation of the sciatic nerve were significantly longer than that in the contralateral VPL nucleus receiving input from the sham-operated side (P<0.05). In contrast, response latencies of LTM and WDR neurons to DC stimulation were not different between the sham operated and CCI sides (0.05). Background activity of WDR neurons was significantly higher in the VPL nucleus contralateral to the CCI side when compared to neurons in the VPL nucleus contralateral to the sham operated side and in naive animals. Responses of LTM and WDR neurons to innocuous mechanical stimulation of the receptive fields were significantly decreased after DC and DC+gracile nucleus lesions in all animals. However, the responses of WDR neurons to noxious stimuli were selectively reduced only in rats with CCI by DC and DC+gracile nucleus lesions (P<0.05). The decrease in noxious stimulus-evoked responses of WDR neurons in the VPL nucleus contralateral to the CCI side after DC and DC+gracile nucleus lesions was greater than that in the VPL nucleus contralateral to the sham operated side and naive animals. These results indicated that DC and DC+gracile nucleus lesions produced selective and stronger effect on noxious responses of VPL nucleus WDR neurons receiving input from the site of nerve injury. The findings suggest that the gracile nucleus-thalamic pathway conveys, or modulates, nociceptive information to the VPL nucleus following peripheral nerve injury, resulting in an increase in VPL nucleus response to noxious stimuli that contributes to the development of mechanical hyperalgesia.     

Differential effects of subcutaneous injection of formalin and bee venom on responses of wide-dynamic-range neurons in spinal dorsal horn of the rat

By using extracellular single unit recording technique, the effects of subcutaneous (s.c.) administration of formalin and bee venom on responses of wide-dynamic-range (WDR) neurons in the spinal dorsal horn were investigated in pentobarbital anaesthetised rats. Similar to the previous results, s.c. formalin injection into the cutaneous receptive field (RF) of WDR neurons produced a biphasic increase in spike response; however, s.c. bee venom injection into the RF produced a prolonged, monophasic increase in spike discharges over the background activity, suggesting that the two tonic pain models may have different underlying neural mechanisms.     

晚期周围神经损伤后感觉功能恢复中:脊髓后角P物质及降钙素基因相关肽的变化

背景晚期周围神经损伤有无修复价值?如果脊髓神经元中P物质和降钙素基因相关肽的变化发生了不可逆的变化,其修复后也预示着感觉功能的缺失. 目的定量研究周围神经损伤24周后,脊髓后角中P物质和降钙素基因相关肽的变化.设计建立以大鼠坐骨神经损伤为研究对象的实验模型,损伤后24周为最远期观察点,自身对照(对侧空白组),定量化研究.单位第四军医大学骨科研究所.材料实验于2002-10/2003-05在第四军医大学骨科研究所完成.SD大鼠55只,分成11组,即坐骨神经切断1,2,3,4,6,8,10,12,16,20,24周各组.干预切断大鼠一侧坐骨神经并结扎其近端的方法建立周围神经损伤模型;另一侧为对照侧.应用计算机图像分析技术测试P物质和降钙素基因相关肽免疫反应区的面积.主要观察指标各组大鼠脊髓后角中P物质和降钙素基因相关肽阳性纤维的终末分布面积的变化.结果55只大鼠均进入结果分析.①P物质时间序列表示周围神经损伤后2～6周,P物质在脊髓后角免疫反应区面积下降至最低,随之回升,至16周恢复正常,20,24周无明显的进一步变化.②脊髓后角降钙素基因相关肽阳性纤维和终末分布面积损伤与自身对照侧的比值1周时1.14,6周时1.13,24周时0.29,各时间点基本相似(P＞0.05)结论周围神经损伤至晚期,脊髓后角及后根神经节细胞合成和分泌P物质及降钙素基因相关肽的功能尚未受到破坏,脊髓后角已处于一种稳定的平衡状态,仍有恢复感觉功能的神经学基础.     

过度通气对在体大鼠脊髓背角WDR神经元兴奋性影响的实验研究

目的:考察过度通气对大鼠脊髓背角广动力范围(Wide dynamic range,WDR)神经元自发和疼痛诱发放电频率的影响。方法:将25只SD大鼠随机分为N(正常通气)和H(过度通气)两组。两组均在吸入麻醉下行椎板切除,记录与大鼠后足掌部皮肤感觉对应的脊髓背角WDR神经元放电频率百分比。N组正常通气120分钟,旨在排除手术创伤对WDR神经元的影响;H组实施过度通气60分钟后,恢复正常通气继续观察60分钟,目的为考察过度通气对该神经元电活动的影响。结果:(1)N组各采样点间WDR神经元自发和诱发放电频率百分比均无显著性差异。(2)H组过度通气后WDR神经元自发和疼痛诱发放电频率百分比较对照值显著降低,并随正常通气的恢复而恢复。(3)H组过度通气期间WDR神经元自发及诱发放电频率百分比均较N组相应时间点显著降低。结论:过度通气可使大鼠脊髓背角WDR神经元兴奋性降低。     

Involvement of solitary tract nucleus in control of nociceptive transmission in cat spinal cord neurons

In cats anesthetized with Nembutal and immobilized with Flaxedil, extracellular recordings were made from dorsal horn neurons and lamina X neurons in the lumbar spinal cord. The nociceptive responses of these neurons elicited by peripheral nerve stimulation were significantly inhibited by stimulation of the nucleus tractus solitarius (NTS) at low intensity without any noticeable cardiovascular reaction. As usual, the late response or C-response was found to be preferentially inhibited by NTS stimulation as compared with the early response or A-response. The effective current intensity for NTS stimulation-produced inhibition ranged from 80 μA to 200 μA. Stronger inhibition was induced when the stimulating site was within or in the immediate vicinity of the NTS. There was no significant difference in the efficacy of the NTS stimulation-produced inhibition of nociceptive response between dorsal horn neurons and lamina X neurons. A similar inhibitory effect was elicited by microinjection of monosodium glutamate into the NTS area.

The results demonstrate that the NTS may be involved in the control of nociceptive transmission at the spinal cord level.     

Nerve injury-induced tactile allodynia is present in the absence of FOS labeling in retrogradely labeled post-synaptic dorsal column neurons

The dorsal column pathway consists of direct projections from primary afferents and of ascending fibers of the post-synaptic dorsal column (PSDC) cells. This pathway mediates touch but may also mediate allodynia after nerve injury. The role of PSDC neurons in nerve injury-induced mechanical allodynia is unknown. Repetitive gentle, tactile stimulus or noxious pinch was applied to the ipsilateral hindpaw of rats with spinal nerve ligation (SNL) or sham surgery that had previously received tetramethylrhodamine dextran in the ipsilateral n. gracilis. Both touch and noxious stimuli produced marked increases in FOS expression in other cells throughout all laminae of the ipsilateral dorsal horn after nerve injury. However, virtually none of the identified PSDC cells expressed FOS immunofluorescence in response to repetitive touch or pinch in either the nerve-injured or sham groups. In contrast, labeled PSDC cells expressed FOS in response to ureter ligation and labeled spinothalamic tract (STT) cells expressed FOS in response to noxious pinch. Identified PSDC neurons from either sham-operated or SNL rats did not express immunoreactivity to substance P, CGRP, NPY, PKCY, MOR, the NK1 and the NPY-Y1 receptor. Retrogradely labeled DRG cells of nerve injured rats were large diameter neurons, which expressed NPY, but no detectable CGRP or substance P. Spinal nerve injury sensitizes neurons in the spinal dorsal horn to repetitive light touch but PSDC neurons apparently do not participate in touch-evoked allodynia. Sensitization of these non-PSDC neurons may result in activation of projections integral to the spinal/supraspinal processing of enhanced pain states and of descending facilitation, thus priming the central nervous system to interpret tactile stimuli as being aversive.     

Different effects of opioid and cannabinoid receptor agonists on C-fiber-induced extracellular signal-regulated kinase activation in dorsal horn neurons in normal and spinal nerve-ligated rats

Nerve injury results in neuropathic pain, a debilitating pain condition. Whereas cannabinoids are consistently shown to attenuate neuropathic pain, the efficacy of opioids is highly controversial. Molecular mechanisms underlying analgesic effects of opioids and cannabinoids are not fully understood. We have shown that the signaling molecule ERK (extracellular signal-regulated kinase) is activated by C-fiber stimulation in dorsal horn neurons and contributes to pain sensitization. In this study, we examined whether opioids and cannabinoids can affect C-fiber-induced ERK phosphorylation (pERK) in dorsal horn neurons in spinal cord slices from normal and spinal nerve-ligated rats. In normal control spinal slices, capsaicin induced a drastic pERK expression in superficial dorsal horn neurons, which was suppressed by morphine (10 microM), the selective mu-opioid receptor agonist DAMGO [[d-Ala2, N-Me-Phe4, Gly5-ol]-enkephalin (1 microM)], and the selective CB1 receptor ACEA agonist [arachidonyl-2'-chloroethylamide (5 microM)]. One week after spinal nerve ligation when neuropathic pain is fully developed, capsaicin induced less pERK expression in the injured L(5)-spinal segment. This pERK induction was not suppressed by morphine (10 microM) and DAMGO (1 microM) but was enhanced by high concentration of DAMGO (5 microM). In contrast, ACEA (10 microM) was still very effective in inhibiting capsaicin-induced pERK expression. In the adjacent L(4) spinal segment, both DAMGO and ACEA significantly suppressed pERK induction by capsaicin. These results indicate that, after nerve injury, opioids lose their capability to suppress C-fiber-induced spinal neuron activation in the injured L(5) but not in the intact L(4) spinal segment, whereas cannabinoids still maintain their efficacy.     

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

In superficial layers of the lumbar spinal dorsal horn, N-methyl-D-aspartate-dependent long-term potentiation (LTP) of C fibre-evoked field potentials, a synaptic model of central sensitisation and hyperalgesia, ensues the application of electrical high-frequency, high-intensity conditioning stimulation to the sciatic nerve. In order to investigate the putative involvement of the G protein-coupled metabotropic glutamate receptors (mGluRs) in the induction of this form of LTP, we applied a series of mGluR antagonists exhibiting distinct group-specific activity profiles to the spinal lumbar enlargement, prior to conditioning stimulation. The group I (mGluR1/5) and group II (mGluR2/3) mGluR antagonist (S)-alpha-methyl-4-carboxyphenylglycine or the selective mGluR1/5 antagonist (S)-4-carboxyphenylglycine consistently impaired the development of spinal LTP. However, potentiation occurred in the presence of the inactive enantiomer (R)-alpha-methyl-4-carboxyphenylglycine. LTP proved insensitive to the selective mGluR2/3 antagonists (2S)-alpha-ethylglutamic acid and LY341495, either spinally or intravenously delivered. LTP could also be induced in the presence of the selective group III (mGluR4/mGluR6-mGluR8) mGluR antagonist (RS)-alpha-methylserine-O-phosphate. However, none of the mGluR-active compounds alone noticeably altered the amplitudes of C fibre-evoked field potentials in the absence of conditioning stimulation. These findings suggest that the induction of LTP of C fibre-evoked field potentials in the spinal dorsal horn by high-frequency, high-intensity stimulation of afferent C fibres requires a group-specific mGluR recruitment, activation of mGluR1/5 but not that of mGluR4/6-8 and mGluR2/3 being a requisite step.