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Spinal antiallodynia action of glycine transporter inhibitors in neuropathic pain models in mice.
J Pharmacol Exp Ther 2008; 326(2):633-45JP

Abstract

Neuropathic pain is refractory against conventional analgesics, and thus novel medicaments are desired for the treatment. Glycinergic neurons are localized in specific brain regions, including the spinal cord, where they play an important role in the regulation of pain signal transduction. Glycine transporter (GlyT)1, present in glial cells, and GlyT2, located in neurons, play roles in modulating glycinergic neurotransmission by clearing synaptically released glycine or supplying glycine to the neurons and thus could modify pain signal transmission in the spinal cord. In this study, we demonstrated that i.v. or intrathecal administration of GlyT1 inhibitors, cis-N-methyl-N-(6-methoxy-1-phenyl-1,2,3,4-tetrahydronaphthalen-2-yl methyl)amino methylcarboxylic acid (ORG25935) or sarcosine, and GlyT2 inhibitors, 4-benzyloxy-3,5-dimethoxy-N-[1-(dimethylaminocyclopently)-methyl]benzamide (ORG25543) and (O-[(2-benzyloxyphenyl-3-fluorophenyl)methyl]-L-serine) (ALX1393), or knockdown of spinal GlyTs by small interfering RNA of GlyTs mRNA produced a profound antiallodynia effect in a partial peripheral nerve ligation model and other neuropathic pain models in mice. The antiallodynia effect is mediated through spinal glycine receptor alpha3. These results established GlyTs as the target molecules for the development of medicaments for neuropathic pain. However, these manipulations to stimulate glycinergic neuronal activity were without effect during the 4 days after nerve injury, whereas manipulations to inhibit glycinergic neuronal activity protected against the development of allodynia in this phase. The results implied that the timing of medication with their inhibitors should be considered, because glycinergic control of pain was reversed in the critical period of 3 to 4 days after surgery. This may also provide important information for understanding the underlying molecular mechanisms of the development of neuropathic pain.

Authors+Show Affiliations

Department of Pharmacology, Division of Integrated Medical Science, Hiroshima University Graduate School of Biomedical Sciences, Kasumi 1-2-3, Minami-ku, Hiroshima 734-8553, Japan.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18448867

Citation

Morita, Katsuya, et al. "Spinal Antiallodynia Action of Glycine Transporter Inhibitors in Neuropathic Pain Models in Mice." The Journal of Pharmacology and Experimental Therapeutics, vol. 326, no. 2, 2008, pp. 633-45.
Morita K, Motoyama N, Kitayama T, et al. Spinal antiallodynia action of glycine transporter inhibitors in neuropathic pain models in mice. J Pharmacol Exp Ther. 2008;326(2):633-45.
Morita, K., Motoyama, N., Kitayama, T., Morioka, N., Kifune, K., & Dohi, T. (2008). Spinal antiallodynia action of glycine transporter inhibitors in neuropathic pain models in mice. The Journal of Pharmacology and Experimental Therapeutics, 326(2), pp. 633-45. doi:10.1124/jpet.108.136267.
Morita K, et al. Spinal Antiallodynia Action of Glycine Transporter Inhibitors in Neuropathic Pain Models in Mice. J Pharmacol Exp Ther. 2008;326(2):633-45. PubMed PMID: 18448867.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Spinal antiallodynia action of glycine transporter inhibitors in neuropathic pain models in mice. AU - Morita,Katsuya, AU - Motoyama,Naoyo, AU - Kitayama,Tomoya, AU - Morioka,Norimitsu, AU - Kifune,Koki, AU - Dohi,Toshihiro, Y1 - 2008/04/30/ PY - 2008/5/2/pubmed PY - 2008/8/13/medline PY - 2008/5/2/entrez SP - 633 EP - 45 JF - The Journal of pharmacology and experimental therapeutics JO - J. Pharmacol. Exp. Ther. VL - 326 IS - 2 N2 - Neuropathic pain is refractory against conventional analgesics, and thus novel medicaments are desired for the treatment. Glycinergic neurons are localized in specific brain regions, including the spinal cord, where they play an important role in the regulation of pain signal transduction. Glycine transporter (GlyT)1, present in glial cells, and GlyT2, located in neurons, play roles in modulating glycinergic neurotransmission by clearing synaptically released glycine or supplying glycine to the neurons and thus could modify pain signal transmission in the spinal cord. In this study, we demonstrated that i.v. or intrathecal administration of GlyT1 inhibitors, cis-N-methyl-N-(6-methoxy-1-phenyl-1,2,3,4-tetrahydronaphthalen-2-yl methyl)amino methylcarboxylic acid (ORG25935) or sarcosine, and GlyT2 inhibitors, 4-benzyloxy-3,5-dimethoxy-N-[1-(dimethylaminocyclopently)-methyl]benzamide (ORG25543) and (O-[(2-benzyloxyphenyl-3-fluorophenyl)methyl]-L-serine) (ALX1393), or knockdown of spinal GlyTs by small interfering RNA of GlyTs mRNA produced a profound antiallodynia effect in a partial peripheral nerve ligation model and other neuropathic pain models in mice. The antiallodynia effect is mediated through spinal glycine receptor alpha3. These results established GlyTs as the target molecules for the development of medicaments for neuropathic pain. However, these manipulations to stimulate glycinergic neuronal activity were without effect during the 4 days after nerve injury, whereas manipulations to inhibit glycinergic neuronal activity protected against the development of allodynia in this phase. The results implied that the timing of medication with their inhibitors should be considered, because glycinergic control of pain was reversed in the critical period of 3 to 4 days after surgery. This may also provide important information for understanding the underlying molecular mechanisms of the development of neuropathic pain. SN - 1521-0103 UR - https://www.unboundmedicine.com/medline/citation/18448867/Spinal_antiallodynia_action_of_glycine_transporter_inhibitors_in_neuropathic_pain_models_in_mice_ L2 - http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=18448867 DB - PRIME DP - Unbound Medicine ER -