Inhibition of spinal N-acetylated-α-linked acidic dipeptidase produces an antinociceptive effect in the rat formalin test
Section snippets
Experimental procedures
The following investigations were carried out under a protocol approved by the Institutional Animal Care Committee, Chiba University. All efforts were made to minimize animal suffering and to reduce the number of animals used. Male Sprague–Dawley rats (250–300 g, Japan SLC, Shizuoka, Japan) were prepared with i.t. catheters and examined for the effects of the agent on the formalin test and the hot plate test.
Behavioral analysis
After the i.t. injection of either 2-PMPA or saline, all animals scored 2 (normal motor function) in the placing/stepping reflex and righting reflex tests.
Formalin test
In the saline-treated rats, a s.c. injection of formalin resulted in a highly reliable biphasic display of flinching of the injected paw (Fig. 1), and this behavior was comparable to that previously reported.24., 27.
In the pre-treatment study, i.t. administered 2-PMPA decreased the level of the sum of instances of flinching in both phases 1
Discussion
In the present study, we clearly demonstrated that pre-treatment with 2-PMPA depressed both the phase 1 and 2 flinching behavior in a dose dependent manner at a dose between 1 and 100 μg. 2-PMPA inhibited phase 2 responses with a greater potency than phase 1; at a dose of 10 μg inhibition of phase 2 responses was significantly greater than that of phase 1 responses, whilst a comparable inhibition of both phases was produced by 100 μg. Intraperitoneal injection of 100 μg of 2-PMPA had no effect on
Conclusions
Intrathecal injection of 2-PMPA, an inhibitor of NAALADase, depressed the phase 1 and 2 flinching behavior in the rat formalin test. Intrathecal injection of 2-PMPA may produce NMDA receptor antagonism and inhibition of transmitter release via activation of mGluR3. These two mechanisms may produce a pronounced inhibition of both phases of the formalin response. These data suggest a new potential dual therapeutic approach to treating pain caused by inflammation.
Acknowledgements
We thank professor Takashi Nishino, Department of Anesthesiology, School of Medicine, Chiba University for his generous support of our study. This study was supported in part by a Grant-in-Aid for Scientific Research (B) of Japan 12470315.
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Still NAAG'ing After All These Years. The Continuing Pursuit of GCPII Inhibitors.
2016, Advances in PharmacologyCitation Excerpt :Multiple GCPII inhibitors have shown efficacy in acute and inflammatory pain models, with 2-PMPA being the most extensively studied (Yamamoto, Nozaki-Taguchi, & Sakashita, 2001; Zhou et al., 2005). 2-PMPA applied intrathecally (i.t.) reduces nociceptive behaviors in the rat formalin and carrageenan models (Yamamoto, Nozaki-Taguchi, & Sakashita, 2001; Yamamoto, Nozaki-Taguchi, Sakashita, & Inagaki, 2001). Intracerebroventricular (i.c.v.) 2-PMPA produces analgesia to formalin (Yamamoto, Kozikowski, Zhou, & Neale, 2008) and spinal application reduces wind-up sensitization phenomena after carrageenan inflammation (Carpenter et al., 2003).
Bioanalytical method for evaluating the pharmacokinetics of the GCP-II inhibitor 2-phosphonomethyl pentanedioic acid (2-PMPA)
2014, Journal of Pharmaceutical and Biomedical AnalysisCitation Excerpt :2-PMPA has shown remarkable specificity for GCP-II with no apparent affinity for over 100 different receptors, ion channels, transporters, and enzymes including several glutamatergic sites such as NMDA, AMPA, and metabotropic glutamate receptors [4]. 2-PMPA has been evaluated in several in vitro and in vivo models of neurological and psychiatric disorders, where it has been demonstrated to decrease extracellular glutamate and/or provide therapeutic benefit in models of ischemic brain injury [4,6], neuropathic pain [7–9], peripheral neuropathies [7,9], formalin-induced agitation [10], seizures [11,12], morphine tolerance [13], cocaine-associated sensitization [14], amyotrophic lateral sclerosis [15], and most recently in cognition dysfunction associated with multiple sclerosis [16]. Although the utility 2-PMPA has been demonstrated in several animal models of disease the compound's extreme hydrophilic nature has impeded its development as a therapeutic drug.
Progress in the discovery and development of glutamate carboxypeptidase II inhibitors
2007, Drug Discovery TodayThe preventive and therapeutic effects of GCPII (NAALADase) inhibition on painful and sensory diabetic neuropathy
2006, Journal of the Neurological Sciences