Spinal N-acetyl-α-linked acidic dipeptidase (NAALADase) inhibition attenuates mechanical allodynia induced by paw carrageenan injection in the rat

Yamamoto, Tatsuo; Nozaki-Taguchi, Natsuko; Sakashita, Yoshihiko

doi:10.1016/s0006-8993(01)02650-6

Cited by 61 publications

(51 citation statements)

References 30 publications

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“…12 Intrathecal administration of NAAG peptidase inhibitors produces an analgesic effect in both inflammatory pain models and in neuropathic pain models. [13][14][15][16] Taken together, these data support the hypothesis that α-2 adrenergic receptor agonists, NMDA receptor antagonists, and NAAG peptidase inhibitors may have some analgesic effects on bone cancer pain. At present, however, the efficacy of these drugs on bone cancer pain has not been examined comprehensively.…”

Section: Conclusion : Les Agonistes α-2 Produisent Un Effet Analgésiqsupporting

confidence: 74%

“…We previously reported that intrathecal administration of 2-(phosphonomethyl)pentanedioic acid, a NAAG peptidase inhibitor, produces an analgesic effect in the rat formalin test and carrageenan test, with a bell-shaped dose-response curve. 13,14 We do not know the mechanisms underlying the dose-response curves for these two structurally different NAAG peptidase inhibitors in these pain models. It has been reported that a high concentration of NAAG acts as a NMDA receptor agonist.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Regional Anesthesia and Pain

Saito

Aoe

Kozikowski

et al. 2006

Can J Anesth/J Can Anesth

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Purpose: Not all bone cancer pain can be effectively treated with current therapies. In the present study, the effects of ip administration of α-2 agonists (dexmedetomidine and clonidine), N-methyl-D-aspartate (NMDA) antagonists (MK-801 and ketamine), an N-acetylaspartylglutamate peptidase inhibitor (ZJ-43), and morphine were examined in a mouse bone cancer pain model. Methods:A bone cancer pain model was produced by injection of murine sarcoma cells into the medullary cavity of the distal femur. To estimate the level of bone cancer pain, the number of pain-related behaviours induced by repeated applications of a von Frey monofilament (0.166 g) to the site of tumour cells implantation was counted. Drugs were administered two weeks after the implantation.Results: Morphine produced a significant analgesic effect (P < 0.001). The α-2 agonists produced analgesic effects (P < 0.001) with an efficacy similar to that of morphine, but only at doses that produced severe sedation. MK-801 had only limited analgesic effects, while ketamine produced an analgesic effect (P < 0.001) with the same efficacy as morphine. ZJ-43 (100 mg·kg -1 ) had a significant analgesic effect (P < 0.05) and the effect of ZJ-43 was antagonized by the selective group II metabotropic glutamate receptor (mGluR) antagonist. Conclusion:These data suggest that α-2 agonists produce an analgesic effect only at a sedative dose and that ketamine, but not MK-801, is associated with an analgesic response without overt side effects. The effect of ZJ-43 is mediated by activating group II mGluRs. Objectif : Les douleurs du cancer des os ne sont pas toujours soulagées par les traitements habituels. Dans la présente étude, les effets de l'administration ip d'agonistes α-2 (dexmédétomi-dine et clonidine), d'antagonistes N-méthyl-D-aspartate (NMDA) (MK-801 et kétamine), d'un inhibiteur de N-acétylaspartylgluta-mate peptidase (ZJ-43) et de morphine ont été examinés dans un modèle de douleur du cancer des os chez la souris. Méthode : Un modèle de douleur du cancer des os a été produit en injectant des cellules de sarcome d'Ewing dans la cavité médul-laire distale du fémur. Pour évaluer le niveau de douleur, nous avons calculé le nombre de mouvements reliés à la douleur induite par l'application répétée d'un monofilament von Frey (0,166 g) au site de la tumeur implantée. Les médicaments ont été administrés deux semaines après l'implantation.Résultats : La morphine a produit une analgésie significative (P < 0,001). Les agonistes α-2 ont produit une analgésie (P < 0,001) similaire à celle de la morphine, mais seulement à des doses produisant une sédation importante. Le MK-801 a eu un effet limité et la kétamine a produit une analgésie aussi efficace que celle de la morphine (P < 0,001). ) a eu un effet analgésique significatif (P < 0,05)

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Section: Conclusion : Les Agonistes α-2 Produisent Un Effet Analgésiqsupporting

confidence: 74%

Section: Discussionmentioning

confidence: 99%

Regional Anesthesia and Pain

Saito

Aoe

Kozikowski

et al. 2006

Can J Anesth/J Can Anesth

Self Cite

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“…As mentioned earlier, Yamamoto et al (2001a) suggested that NAAG acts as an NMDA receptor antagonist at low concentrations, but as a low potency NMDA receptor agonist at high concentrations. If this hypothesis were correct, it could be speculated that administration of a high dose (100 mg/kg) of 2-PMPA leads to high concentrations of NAAG that acts as an agonist, rather than an antagonist at NMDA receptors, and thus increases the severity of morphine withdrawal.…”

Section: Effects Of Gcp II Inhibition On Morphine Dependence/ Withdrawalmentioning

confidence: 77%

“…However, in many other systems it has been shown to antagonize the effects of NMDA receptor activation (Burlina et al, 1994 ;Grunze et al, 1996 ;Puttfarcken et al, 1993 ), and therefore, according to these findings, an inhibition of its metabolism would actually inhibit NMDA receptors. Thus, as noted by Yamamoto et al (2001a) NAAG acts as an NMDA receptor antagonist at low concentrations but as a low-potency NMDA receptor agonist at high concentrations, and can be regarded as a mixed agonist/antagonist at the NMDA receptor depending on its concentration (Bruno et al, 1998;Thomas et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Morphine Tolerance and Reward but not Expression of Morphine Dependence are Inhibited by the Selective Glutamate Carboxypeptidase II (GCP II, NAALADase) Inhibitor, 2-PMPA

Popik

Kozela

Wróbel

et al. 2002

Neuropsychopharmacol

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Inhibition of glutamate carboxypeptidase II (GCP II; NAALADase) produces a variety of effects on glutamatergic neurotransmission. The aim of this study was to investigate effects of GCP II inhibition with the selective inhibitor, 2-PMPA, on: (a) development of tolerance to the antinociceptive effects, (b) withdrawal, and (c) conditioned reward produced by morphine in C57/Bl mice. The degree of tolerance was assessed using the tail-flick test before and after 6 days of twice daily (b.i.d.) administration of 2-PMPA and 10 mg/kg of morphine. Opioid withdrawal was measured 3 days after twice daily morphine (30 or 10 mg/kg) administration, followed by naloxone challenge. Conditioned morphine reward was investigated using conditioned place preference with a single morphine dose (10 mg/kg). High doses of 2-PMPA inhibited the development of morphine tolerance (resembling the effect of 7.5 mg/kg of the NMDA receptor antagonist, memantine) while not affecting the severity of withdrawal. A high dose of 2-PMPA (100 mg/kg) also significantly potentiated morphine withdrawal, but inhibited both acquisition and expression of morphine-induced conditioned place preference. Memantine inhibited the intensity of morphine withdrawal as well as acquisition and expression of morphine-induced conditioned place preference. In addition, 2-PMPA did not affect learning or memory retrieval in a simple two-trial test, nor did it produce withdrawal symptoms in morphinedependent, placebo-challenged mice. Results suggest involvement of GCP II (NAALADase) in phenomena related to opioid addiction.

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“…E2072's analgesic effect, once present, however, was maintained for up to 7 days after E2072's ability to reduce established thermal hyperalgesia after loose sciatic nerve ligation is in agreement with previous reports of GCPII inhibition in other pain models. For example, spinal delivery of the GCPII inhibitor 2-(phosphonomethyl)pentanedioic acid (2-PMPA) (Jackson et al, 2001) was found to attenuate nociception in the hot plate and formalin pain test (Yamamoto et al, 2001). Intraperitoneal 2-PMPA was found to attenuate allodynia and accompanying increased ectopic discharges after partial sciatic nerve ligation in a model of neuropathic pain (Chen et al, 2002), as well as reduced mechanical allodynia in rats receiving carrageenan (Yamamoto et al, 2001) or unilateral sciatic nerve ligation (Nagel et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

The Orally Active Glutamate Carboxypeptidase II Inhibitor E2072 Exhibits Sustained Nerve Exposure and Attenuates Peripheral Neuropathy

Wozniak

Wu²,

Vornov

et al. 2012

J Pharmacol Exp Ther

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Peripheral neuropathy from nerve trauma is a significant problem in the human population and often constitutes a doselimiting toxicity in patients receiving chemotherapy. (3-2-Mercaptoethyl)biphenyl-2,3-dicarboxylic acid (E2072) is a potent (K i ϭ 10 nM), selective, and orally available inhibitor of glutamate carboxypeptidase II (GCPII). Here, we report that E2072 attenuates hyperalgesia and nerve conduction velocity deficits in preclinical rodent models of neuropathic pain and oxaliplatininduced neuropathy. In the chronic constrictive injury model, orally administered E2072 reversed pre-existing thermal hyperalgesia in rats in a dose-dependent fashion with a minimally effective dose of 0.1 mg/kg/day. It is noteworthy that multiple days of dosing of E2072 were required before analgesia was realized even though GCPII inhibitory exposures were achieved on the first day of dosing. In addition, analgesia was found to persist for up to 7 days after cessation of dosing, consistent with E2072's pharmacokinetic profile and sustained exposure. Furthermore, in a chronic oxaliplatin-induced neuropathy model (6 mg/kg i.p. oxaliplatin twice weekly for 4 weeks), female BALB/c mice receiving daily oral E2072 at 1.0 and 0.1 mg/kg displayed no deficits in either caudal or digital velocity compared with significant deficits observed in mice treated with oxaliplatin alone (12 Ϯ 3 and 9 Ϯ 2%, respectively). Similar findings were seen with oxaliplatin-induced digital and caudal amplitude deficits. It is noteworthy that E2072 showed no interference with the antineoplastic efficacy of oxaliplatin in mice bearing leukemia (L1210), even at doses 100 times its neuroprotective/analgesic dose, indicating a selective effect on neuropathy. These data support the therapeutic utility of GCPII inhibitors in neuropathy and neuropathic pain.

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Spinal N-acetyl-α-linked acidic dipeptidase (NAALADase) inhibition attenuates mechanical allodynia induced by paw carrageenan injection in the rat

Cited by 61 publications

References 30 publications

Regional Anesthesia and Pain

Regional Anesthesia and Pain

Morphine Tolerance and Reward but not Expression of Morphine Dependence are Inhibited by the Selective Glutamate Carboxypeptidase II (GCP II, NAALADase) Inhibitor, 2-PMPA

The Orally Active Glutamate Carboxypeptidase II Inhibitor E2072 Exhibits Sustained Nerve Exposure and Attenuates Peripheral Neuropathy

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