Spinal Glutamate Release Research Articles

Preclinical study in a postoperative pain model to investigate the action of ketamine, lidocaine, and ascorbic acid in reversing fentanyl-induced, non-glutamate-dependent hyperalgesia.

Opioid-induced hyperalgesia (OIH) is a paradoxical phenomenon in which exposure to opioids can increase sensitivity to painful stimuli. Currently, several drugs have been used in an attempt to prevent OIH. We design this study to address the effect of preemptive treatment with ketamine, lidocaine, and ascorbic acid in a rat preclinical model of perioperative opioid-induced hyperalgesia. To reproduce OIH in a model of postoperative pain, rats received successive doses of fentanyl subcutaneously and underwent an incision in the paw. In an attempt to prevent OIH, ketamine, lidocaine, and ascorbic acid were administered before treatment with fentanyl. The von Frey test and the hot-plate test were used to evaluate mechanical allodynia and thermal hyperalgesia, respectively, with a follow-up period from 1 hour up to 7 days after surgery. Spinal cord nerve terminals (synaptosomes) were used to assess glutamate release under our experimental conditions. Consecutive fentanyl injections increased the postoperative pain as indicated by increased thermal hyperalgesia and allodynia 48 hours after incision. Ketamine, lidocaine, and the combination of ketamine + lidocaine were able to prevent thermal hyperalgesia but not mechanical allodynia. Ascorbic acid did not prevent the hyperalgesia induced by fentanyl. We found no correlation between spinal glutamate release and the pharmacological treatments. Fentanyl induced a hyperalgesic effect that last few days in a postoperative model of pain. Hyperalgesic effect was not totally inhibited by ketamine and lidocaine in rats. Increased glutamate release was not the main molecular mechanism of fentanyl-induced hyperalgesia.

High-frequency spinal cord stimulation treatment attenuates the increase in spinal glutamate release and spinal miniature excitatory postsynaptic currents in rats with spared nerve injury-induced neuropathic pain

High-frequency spinal cord stimulation (HFSCS) at 10 kHz provides paresthesia-free treatment for chronic pain. However, the underlying mechanisms of its action have not been fully elucidated. The aim of the present study was to investigate the effect of HFSCS treatment on spinal glutamate release and uptake in spared nerve injury (SNI) rats. HFSCS was applied to the T10/T11 spinal cord 3 days after SNI. The concentration of spinal glutamate, glutamate transporter activity and miniature excitatory postsynaptic currents (mEPSCs) from neurons in lamina II were evaluated. HFSCS treatment alleviated SNI pain induced by mechanical and cold allodynia. HFSCS treatment also partially restored altered spinal glutamate uptake activity, the levels of spinal glutamate, and the frequency of mEPSCs following SNI. In conclusion, HFSCS treatment attenuated SNI-induced neuropathic pain and partially restored the altered glutamate uptake after SNI.

Pulsed radiofrequency attenuates diabetic neuropathic pain and suppresses formalin-evoked spinal glutamate release in rats.

BACKGROUND: Pulsed radiofrequency (PRF) has been used to treat chronic pain for years, but its effectiveness and mechanism in treating diabetic neuropathic pain are still unexplored. The aim of this study was to elucidate the modulation of diabetic neuropathic pain induced by streptozotocin and the release of spinal excitatory amino acids by PRF.METHODS: Diabetes was induced by intraperitoneal administration of streptozotocin. Pulsed radiofrequency was applied to L5 and L6 dorsal roots at 42 °C for 2 min. The responses of all of the groups to thermal, mechanical and cold stimuli were measured for a period of 6 d after this process. Seven days after PRF treatment, intrathecal microdialysis was used to examine the effect of pulsed radiofrequency on the formalin-evoked spinal release of excitatory amino acids and concurrent behaviour responses from diabetic rats.RESULTS: Three weeks after intraperitoneal streptozotocin treatment and before PRF application, mechanical, thermal and cold hypersensitivity occurred. Application of PRF significantly alleviated hyperglycaemia-induced mechanical, thermal and cold hypersensitivity and also attenuated the increase in formalin-evoked CSF glutamate concentration, compared with sham treated diabetic rats.CONCLUSION: It may be concluded that PRF has an analgesic effect on neuropathic pain by suppressing the nociception-induced release of excitatory neurotransmitters. PRF may provide a novel promising therapeutic approach for managing diabetic neuropathic pain.

Transient Receptor Potential Ankyrin 1 as a Target for Perioperative Pain Management

Transient Receptor Potential Ankyrin 1 as a Target for Perioperative Pain Management

The involvement of the spinal release of glutamate and nitric oxide in peripheral noxious stimulation-induced pain-related behaviors—Study in mouse spinal microdialysis

The quantification of neurotransmitters in the dorsal horn of the spinal cord under pain conditions is important to investigate the mechanism of pain transmission. Microdialysis is widely used for the quantification of the release of endogenous substances in various tissues; however, most of the experiments have been conducted in rats. In the present study, we measured the spinal release of glutamate and NO2/NO3 under pain conditions induced by formalin or capsaicin using mouse spinal microdialysis. We found an association between formalin- or capsaicin-induced nociceptive behaviors and the release of glutamate and NO2/NO3 in the spinal cord.

A-995662 [(R)-8-(4-methyl-5-(4-(trifluoromethyl)phenyl)oxazol-2-ylamino)-1,2,3,4-tetrahydronaphthalen-2-ol], a novel, selective TRPV1 receptor antagonist, reduces spinal release of glutamate and CGRP in a rat knee joint pain model

The TRPV1 antagonist A-995662 demonstrates analgesic efficacy in monoiodoacetate-induced osteoarthritic (OA) pain in rat, and repeated dosing results in increased in vivo potency and a prolonged duration of action. To identify possible mechanism(s) underlying these observations, release of neuropeptides and the neurotransmitter glutamate from isolated spinal cord was measured. In OA rats, basal release of glutamate, bradykinin and calcitonin gene-related peptide (CGRP) was significantly elevated compared to naïve levels, whereas substance P (SP) levels were not changed. In vitro studies showed that capsaicin-evoked TRPV1-dependent CGRP release was 54.7 ± 7.7% higher in OA, relative to levels measured for naïve rats, suggesting that TRPV1 activity was higher under OA conditions. The efficacy of A-995662 in OA corresponded with its ability to inhibit glutamate and CGRP release from the spinal cord. A single, fully efficacious dose of A-995662, 100 μmol/kg, reduced spinal glutamate and CGRP release, while a single sub-efficacious dose of A-995662 (25 μmol/kg) was ineffective. Multiple dosing with A-995662 increased the potency and duration of efficacy in OA rats. Changes in efficacy did not correlate with plasma concentrations of A-995662, but were accompanied with reductions in spinal glutamate release. These findings suggest that repeated dosing of TRPV1 antagonists enhances therapeutic potency and duration of action against OA pain, at least in part, by the sustained reduction in release of glutamate and CGRP from the spinal cord.

Metabotropic glutamate receptors (mGluRs) regulate noxious stimulus‐induced glutamate release in the spinal cord dorsal horn of rats with neuropathic and inflammatory pain

In rats with persistent pain, spinal group I metabotropic glutamate receptor (mGluR) activity has been shown to be pronociceptive, whereas spinal group II/III activity is anti-nociceptive. In brain, group I mGluR activity produces positive feedback effects on glutamate release, whereas group II/III activity produces negative feedback effects. It is unknown whether the nociceptive versus anti-nociceptive effects of spinal group I versus group II/III mGluR activity depend on differential regulation of spinal glutamate release. Here, we used behavioral nociceptive testing and in vivo microdialysis to assess the effect of intrathecal treatment with group I mGluR antagonists [cyclopropan[b] chromen-1a-carboxylate, (CPCCOEt), 2-methyl-6-(phenylethynyl) pyridine (MPEP)] or groups II [aminopyrrolidine-2R,4R-dicarboxylate (APDC)] and III [l-2-amino-4-phosphonobutyrate (l-AP4)] mGluR agonists or vehicle, on nociception and noxious stimulus-induced increases in glutamate release in the spinal cord dorsal horn of rats with a chronic constriction injury (CCI) of the sciatic nerve or hind paw injection of complete Freund's adjuvant (CFA). None of the treatments significantly influenced basal spinal glutamate concentrations in either CCI or CFA rats. In CCI rats, formalin-induced nociception and increases in spinal glutamate concentrations were significantly attenuated by pre-treatment with CPCCOEt, MPEP, APDC, or l-AP4. In CFA rats, capsaicin-induced increases in nociception and spinal glutamate concentrations were significantly attenuated by pre-treatment with CPCCOEt, MPEP, or APDC, but not l-AP4. This study demonstrates that group I antagonists and group II/III mGluR agonists attenuated the enhanced nociception and noxious stimulus-induced glutamate release in spinal cord dorsal horn of CCI and/or CFA rats in vivo, and suggests a possible mechanism for their anti-hyperalgesic effects.

Evidence that pregabalin reduces neuropathic pain by inhibiting the spinal release of glutamate

Pregabalin is an anti-convulsant that successfully treats many neuropathic pain syndromes, although the mechanism of its anti-hyperalgesic action remains elusive. This study aims to help delineate pregabalin's anti-hyperalgesic mechanisms. We assessed the effectiveness of pregabalin at decreasing mechanical and cold hypersensitivity induced in a rat model of neuropathic pain. Thus, we compared the effectiveness of pre- or post-treatment with systemic or intrathecal (i.t.) pregabalin at reducing the development and maintenance of the neuropathic pain symptoms. Pregabalin successfully decreased mechanical and cold hypersensitivity, as a pre-treatment, but was less effective at suppressing cold hypersensitivity when administered as a post-treatment. Furthermore, both i.t. and systemic administration of pregabalin were effective in reducing the behavioral hypersensitivity, with the exception of systemic post-treatment on cold hypersensitivity. We also examined pregabalin's effects at inhibiting hind paw formalin-induced nociception in naïve rats and formalin-induced release of excitatory amino acids in the spinal cord dorsal horn (SCDH) both in naïve rats and in rats with neuropathic pain. Pregabalin dose-dependently reduced nociceptive scores in the formalin test. We also present the first evidence that pregabalin reduces the formalin-induced release of glutamate in SCDH. Furthermore, i.t. pregabalin reduces the enhanced noxious stimulus-induced spinal release of glutamate seen in neuropathic rats. These data suggest that pregabalin reduces neuropathic pain symptoms by inhibiting the release of glutamate in the SCDH.

(622): Augmented evoked spinal glutamate release occurs after paclitaxel therapy: Correlation with pain after chemotherapeutic agents

(622): Augmented evoked spinal glutamate release occurs after paclitaxel therapy: Correlation with pain after chemotherapeutic agents

Different effects of morphine and morphine-6β-glucuronide on formalin-evoked spinal glutamate release in conscious and freely moving rats

The aim of this study was to investigate comparatively the role of spinal glutamate in the antinociceptive effect of morphine and morphine-6β-glucuronide (M6G). The glutamate concentration in the spinal microdialysates and flinching behavior were simultaneously measured in conscious and freely moving rats after the intraplanter injection of formalin. The subcutaneous administration of morphine (0.3–3 mg/kg) in these rats suppressed dose dependently both flinching behavior and spinal glutamate release induced by formalin. Similarly, the subcutaneous administration of M6G at doses of 0.1–3 mg/kg suppressed the formalin-induced flinching behavior in the dose-dependent manner, but it did not cause a dose-related inhibition of spinal glutamate release. The inhibitory effects of morphine on the formalin-induced flinching behavior and spinal glutamate release were markedly attenuated by repeated treatment with this drug for 5 days in rats. Thus, there was a significant ( P < 0.05) correlation between antinociception and inhibitory effect on glutamate release of morphine in rats. These results suggest a significant difference between morphine and M6G in the participation of spinal glutamate for the antinociceptive effect.

A comparison of the glutamate release inhibition and anti‐allodynic effects of gabapentin, lamotrigine, and riluzole in a model of neuropathic pain

The effects of treatment with the anti-convulsant agents, lamotrigine and riluzole were compared with gabapentin in a rat experimental model of neuropathic pain. Rats were treated intraperitoneally, with gabapentin (30, 100 and 300 mg/kg), lamotrigine (2, 10 and 50 mg/kg) or riluzole (6 and 12 mg/kg) prior to, and every 12 h for 4 days following chronic constriction injury (CCI) of the sciatic nerve. Mechanical and cold sensitivity were assessed prior to surgery (baseline) and then at 4, 8 and 12 days following CCI. The four-day treatment with each of the agents was effective at producing reductions in the development of mechanical and cold hypersensitivity for periods ranging from the fourth to 12th day. The highest doses of each of the agents were also assessed on formalin-induced nociceptive behaviors and on formalin-induced increases in extracellular glutamate (Glu) and aspartate (Asp) in the spinal cord dorsal horn (SCDH) of awake behaving rats using in vivo microdialysis. Nociceptive scores in formalin test were significantly decreased by gabapentin (300 mg/kg i.p.) and riluzole (12 mg/kg i.p.), but not by lamotrigine (50 mg/kg i.p.). Formalin-induced increases in glutamate levels in SCDH were lowered significantly, as compared with the controls, with all drugs both in the first phase and second phases, with the greatest effects for riluzole and gabapentin. Similar suppressive effects of the drugs were observed on formalin-induced increases in spinal aspartate, except that gabapentin and lamotrigine produced effects only during the second phase. Riluzole produced profound and prolonged reductions in the spinal levels of glutamate and aspartate both for basal and formalin-stimulated release. In conclusion, the results suggest that the anti-convulsant agents gabapentin, lamotrigine and riluzole may reduce the development of hyperalgesia in a rat model of neuropathic pain by reducing the spinal release of glutamate. Riluzole's pronounced suppressive effects on spinal EAA levels is attributed to its established role as a glutamate release inhibitor and an enhancer of glutamate transporter activity.

Increased Expression of Cyclooxygenase and Nitric Oxide Isoforms, and Exaggerated Sensitivity to Prostaglandin E2, in the Rat Lumbar Spinal Cord 3 Days after L5–L6 Spinal Nerve Ligation

Spinal prostaglandins seem to be important in the early pathogenesis of experimental neuropathic pain. Here, the authors investigated changes in the expression of cyclooxygenase and nitric oxide synthase (NOS) isoforms in the lumbar, thoracic, and cervical spinal cord and the pharmacologic sensitivity to spinal prostaglandin E2 (PGE2) after L5-L6 spinal nerve ligation (SNL). Male Sprague-Dawley rats, fitted with intrathecal catheters, underwent SNL or sham surgery 3 days before experimentation. Paw withdrawal threshold was monitored for up to 20 days. Immunoblotting, spinal glutamate release, and behavioral testing were examined 3 days after SNL. Allodynia (paw withdrawal threshold < or = 4 g) was evident 1 day after SNL and remained stable for 20 days. Paw withdrawal threshold was unchanged (P > 0.05) from baseline (> 15 g) after sham surgery except for a small but significant decrease on day 20. Cyclooxygenase 2, neuronal NOS, and inducible NOS were significantly increased in the ipsilateral lumbar dorsal horn after SNL. Expression in the contralateral dorsal horn and ventral horns (lumbar segments) or bilaterally (thoracic and cervical segments) was unchanged from sham controls. This was accompanied by a significant decrease in both the EC50 of PGE2-evoked glutamate release and the ED50 of PGE2 on brush-evoked allodynia. Enhanced sensitivity to PGE2 was localized to lumbar segments of SNL animals and attenuated by SC-51322 or S(+)-ibuprofen, but not R(-)-ibuprofen (100 mum). The increased expression of cyclooxygense-2, neuronal NOS, and inducible NOS and the enhanced sensitivity to PGE2 in spinal segments affected by SNL support the hypothesis that spinal prostanoids play an early pathogenic role in experimental neuropathic pain.

Evidence that gabapentin reduces neuropathic pain by inhibiting the spinal release of glutamate

Gabapentin is an anticonvulsant that successfully treats many neuropathic pain syndromes, although the mechanism of its antihyperalgesic action remains elusive. This study aims to help delineate gabapentin's antihyperalgesic mechanisms. We assessed the effectiveness of gabapentin at decreasing mechanical and cold hypersensitivity induced in a rat model of neuropathic pain. Thus, we compared the effectiveness of pre- or post-treatment with systemic or intrathecal (i.t.) gabapentin at reducing the development and maintenance of the neuropathic pain symptoms. Gabapentin successfully decreased mechanical and cold hypersensitivity, both as a pretreatment and post-treatment. Furthermore, both i.t. and systemic administration of gabapentin were effective in reducing the behavioral hypersensitivity; however, the i.t. administration was superior to the systemic. We also examined gabapentin's effects at inhibiting hindpaw formalin-induced release of excitatory amino acids (EAAs) in the spinal cord dorsal horn (SCDH) both in naïve rats and in rats with neuropathic pain. We present the first evidence that gabapentin reduces the formalin-induced release of both glutamate and aspartate in SCDH. Furthermore, i.t. gabapentin reduces the enhanced noxious stimulus-induced spinal release of glutamate seen in neuropathic rats. These data suggest that gabapentin reduces neuropathic pain symptoms by inhibiting the release of glutamate in the SCDH.

Paradoxal effect of intrathecal lidocaine on spinal glutamate and prostaglandin E2 release following formalin inflammation

Paradoxal effect of intrathecal lidocaine on spinal glutamate and prostaglandin E2 release following formalin inflammation

Periodic abstinence enhances nociception without significantly altering the antinociceptive efficacy of spinal morphine in the rat

Naloxone administration in the opioid dependent rat is associated with spinal glutamate release and NMDA receptor activation which reportedly is also responsible for opioid tolerance. We hypothesized that episodic withdrawal during chronic infusion of spinal morphine might paradoxically enhance tolerance. Rats (24/group) infused with intrathecal morphine (M) for 4 days (20 nmol/μl per h) were given a daily subcutaneous (s.c.) injection of naloxone 0.6 mg/kg per 0.2 ml (MN) or saline 0.2 ml (MS). A third saline infused group was given daily s.c. saline 0.2 ml (SS). Latencies (rear paw hot box) were tested immediately prior to each daily injection. After termination of each infusion, the dose effect of spinal morphine (0.1, 1, 10, and 100 nmol) was examined. The MN group showed a significantly greater decline in daily latencies compared with the MS group, but also had greater withdrawal hyperalgesia upon termination of the infusion. Dose response to spinal morphine was not significantly different in either MS or MN groups. Periodic abstinence thus enhanced nociception without significantly altering the antinociceptive effect of spinal morphine in this group.

Spinal amino acid release and repeated withdrawal in spinal morphine tolerant rats.

1. We used spinal microdialysis in awake rats to investigate whether the repeated withdrawal with naloxone during continuous spinal infusion of morphine would lead to a progressively greater spinal glutamate release and a more pronounced intrathecal tolerance. 2. Rats received lumbar intrathecal (IT) infusion of morphine (IT-M: 20 nmol microl(-1) h(-1)) or saline (IT-S: 1 microl h(-1)) continuously for 3 days. Both groups were further subdivided to receive intraperitoneal (i.p.) injection of naloxone (IP-N: 0.6 mg kg(-1)) or saline (IP-S: 3 ml kg(-1)) every 24 h after the beginning of IT infusion. Daily thermal escape latencies, withdrawal signs, the resting basal release of spinal amino acids before IP injection and the release immediately after the injection (evoked) were measured. 3. Rats receiving IT morphine showed a maximum increase in thermal escape latency on day 1, after which this value declined, with the fastest decline observed in IT morphine + IP naloxone group. On day 1, no significant difference was observed among groups in the resting basal release of amino acids. Rats in IT morphine + i.p. naloxone group displayed a progressive increase in this value. The release was not significantly altered in other groups. 4. For the IT-M + IP-N group, basal resting dialysate concentrations of Glu, Asp and Tau rose steadily over the 3-day infusion interval. No change in basal resting release was noted for any other treatment. 5. Evoked release (after i.p. naloxone) in IT-M animals displayed a progressive increase over the three repeated exposures. Evoked release did not change significantly in other treatment groups. 6. The degree of precipitated withdrawal significantly correlated with the increase in glutamate acutely evoked by i.p. injection. 7. The present results show that periodic transient withdrawal of spinal opiate agonist activity leads to a progressive increase in glutamate outflow and withdrawal signs, in a manner consistent with an enhanced development of spinal tolerance.

神経因性疼痛の発症・維持機構における脊髄神経可塑性の役割 : 脊髄神経伝達および細胞内シグナリング変調における新規Ca^&lt;2+&gt;チャネル阻害薬の効果

The mechanism of neuropathic pain following peripheral nerve injury has not been fully understood. Recent investigations suggested that glutamate-mediated activation of spinal cord neurons might be a pivotal mechanism to induce central sensitization. Following peripheral nerve injury, glutamatergic neuronal activation evokes repetitive stimulation of targeted receptor, NMDA and AMPA receptors followed by intracellular signaling, including early gene c-fos expression. However, there is no direct observation of spinal glutamate release and c-fos expression in relation to pain behavior. N-type Ca channels are especially located at terminal of c-fiber and Aβ-fiber, and it is thought to modulate afferent nociceptive processing. Therefore, the present study was designed to characterize the effect of a novel N-type Ca channel blocker, ONO-2921 on the thermal hyperalgesia in relation to concomitant spinal CSF glutamate release and expression of c-fos protein of dorsal horn neurons. Male Spague-Dawley rats were intrathecally implanted with microdialysis probe. Three days later, the left sciatic nerve was loosely ligated (chronic constriction injury: CCI). The paw withdrawal latency (PWL) against thermal stimulation was periodically measured after CCI. On days 5 and 10, the intrathecal microdialysis was conducted for measuring CSF glutamate release evoked by thermal stimulation to hind paw. After completion of measurements, per fusion fixation was performed for immunohistochemistry (c-fos protein) and HE stains. ONO-2921 (100 mg, po) alone or together with BayK-8644 (agonist of L-type Ca channel) was periodically given at 5 days after CCI operation. Following CCI the PWL of injured leg was decreased with time observed from day 3 to day 10. On day 10, CSF glutamate releases evoked by thermal stimulation was increased by 20%. The c-fos positive-immunoreactivity at Rexed I-n was profoundly allowed accompanied with neuronal damage of Rexed III-IV. These changes were significantly attenuated with ONO-2921. This effect of ONO-2921 was not reversed by i. t. Bay K-8644. Based on the present study, it is suggested that the increased CSF-glutamate release after peripheral nerve injury may cause perturbation of synaptic transmission, including CSF-glutamate release followed by c-fos expression of neurons which is so-called "neuroplasticity" of spinal cord neuronal system and that this repetitive neuronal activation of wide-dynamic range neurons develops neuropathic pain. A novel N-type Ca channel blocker ONO-2921 has attenuating effect of afferent nociceptive processing which is decrease of CSF glutamate release in relation to c-fos expression.

Intrathecal adenosine A_1 receptor agonist attenuates hyperalgesia without inhibiting spinal glutamate release in the rat

Intrathecal adenosine A_1 receptor agonist attenuates hyperalgesia without inhibiting spinal glutamate release in the rat

Role of presynaptic muscarinic and GABA(B) receptors in spinal glutamate release and cholinergic analgesia in rats.

Spinally administered muscarinic receptor agonists or acetylcholinesterase inhibitors can produce effective pain relief. However, the analgesic mechanisms and the site of actions of cholinergic agents in the spinal cord are not fully understood. In this study, we investigated the mechanisms underlying cholinergic presynaptic regulation of glutamate release onto spinal dorsal horn neurons. The role of spinal GABA(B) receptors in the antinociceptive action of muscarine was also determined. Whole-cell voltage-clamp recordings were performed on visualized dorsal horn neurons in the lamina II in the spinal cord slice preparation of rats. The miniature excitatory postsynaptic currents (mEPSCs) and miniature inhibitory postsynaptic currents (mIPSCs) were recorded in the presence of tetrodotoxin. The evoked EPSCs (eEPSCs) were obtained by electrical stimulation of the dorsal root entry zone or the attached dorsal root. Nociception in rats was measured using a radiant heat stimulus and the effect of intrathecal administration of drugs tested. Acetylcholine (10-100 microM) reduced the amplitude of monosynaptic eEPSCs in a concentration-dependent manner. Acetylcholine also significantly decreased the frequency of non-NMDA receptor-mediated mEPSCs, which was antagonized by atropine but not mecamylamine. The frequency of GABA(A) receptor-mediated mIPSCs was significantly increased by acetylcholine and this excitatory effect was abolished by atropine. Existence of presynaptic M(2) muscarinic receptors in the spinal dorsal horn was further demonstrated by immunocytochemistry staining and dorsal rhizotomy. CGP55845, a GABA(B) receptor antagonist, significantly attenuated the inhibitory effect of acetylcholine on the frequency of mEPSCs and the amplitude of monosynaptic eEPSCs in lamina II neurons. Furthermore, the antinociceptive action produced by intrathecal muscarine was significantly reduced by CGP55845 pretreatment in rats. Therefore, data from this integrated study provide new information that acetylcholine inhibits the glutamatergic synaptic input to lamina II neurons through presynaptic muscarinic receptors. Inhibition of glutamate release onto lamina II neurons by presynaptic muscarinic and GABA(B) heteroreceptors in the spinal cord probably contributes to the antinociceptive action of cholinergic agents.

神経因性疼痛の発症・維持機構における脊髄グルタメート放出の関与 : Cilnidipine による修飾作用

神経因性疼痛の発症・維持機構における脊髄グルタメート放出の関与 : Cilnidipine による修飾作用