Positive N-methyl-d-aspartate receptor modulation by selective glycine transporter-1 inhibition in the rat dorsal spinal cord in vivo

Whitehead, Kevin J.; Pearce, S.; Walker, Glenn; Sundaram, Hardy; Hill, David R.; Bowery, Norman G.

doi:10.1016/j.neuroscience.2004.04.006

Cited by 39 publications

(25 citation statements)

References 57 publications

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“…Glycinergic transmission is increased by the pharmacological blockade of GlyT2 in lamina X neurons of rat spinal cord slices (36). An increase in extracellular glycine was also demonstrated by microdialysis perfusion of the dorsal spinal cord of rats with the GlyT2 inhibitor ORG25543 (37). Taken together, these findings suggest that anti-allodynic effect of intrathecal ALX1393 observed in the present study results from the accumulation of glycine at the glycinergic synaptic cleft and subsequent suppression of excitatory neuronal activities in the spinal dorsal horn.…”

Section: Discussionsupporting

confidence: 76%

“…Intrathecal NMDA-induced dynamic allodynia was inhibited by intrathecal ALX1393, but not sarcosine, supporting the idea that blockade of GlyT1, but not GlyT2, can enhance excitatory effects via glycinemediated activation of NMDA receptors. In fact, a study using microdialysis perfusion of the lumbar spinal cord of rats has demonstrated that the GlyT1 inhibitor ORG24598 increases extracellular glycine accompanied by a progressive increase in citrulline release, an index for the activation of the NMDA/nitric oxide synthase signaling cascade (37). The GlyT2 inhibitor ORG25543 induces a similar increase in glycine levels without affecting citrulline release (37).…”

Section: Discussionmentioning

confidence: 99%

“…In fact, a study using microdialysis perfusion of the lumbar spinal cord of rats has demonstrated that the GlyT1 inhibitor ORG24598 increases extracellular glycine accompanied by a progressive increase in citrulline release, an index for the activation of the NMDA/nitric oxide synthase signaling cascade (37). The GlyT2 inhibitor ORG25543 induces a similar increase in glycine levels without affecting citrulline release (37). With these findings taken into account, the present results suggest that the inhibitory effects of GlyT1 inhibitor are masked by excitatory effects via glycine-mediated activation of NMDA receptors in mice with herpetic or postherpetic allodynia.…”

Section: Discussionmentioning

confidence: 99%

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Blockade of Glycine Transporter (GlyT) 2, but Not GlyT1, Ameliorates Dynamic and Static Mechanical Allodynia in Mice With Herpetic or Postherpetic Pain

2010

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Abstract.Glycine is an inhibitory neurotransmitter in the spinal dorsal horn and its extracellular concentration is regulated by glial glycine transporter (GlyT) 1 and neuronal GlyT2. This study was conducted to elucidate the effects of intrathecal injections of GlyT1 and GlyT2 inhibitors on two distinct types of mechanical allodynia, dynamic and static allodynia, in mice with herpetic or postherpetic pain. The GlyT2 inhibitor ALX1393, but not the GlyT1 inhibitor sarcosine, suppressed dynamic and static allodynia at the herpetic and postherpetic stages. Intrathecal ALX1393 suppressed dynamic allodynia induced by intrathecal strychnine and N -methyl-D -aspartate (NMDA). Intrathecal sarcosine suppressed dynamic allodynia induced by intrathecal strychnine, but not NMDA. Expression level of GlyT1, but not GlyT2, mRNA in the lumbar dorsal horn was decreased at the herpetic and postherpetic stages. Glycine receptor α 1-subunit mRNA was decreased in the lumbar dorsal horn at the herpetic, but not postherpetic stage, without alteration in α 3-subunit mRNA. The results suggest that GlyT2 is a potential target for treatment of dynamic and static allodynia in patients with herpes zoster and postherpetic neuralgia. The lack of efficacy of GlyT1 inhibitor may be explained by activation of NMDA receptors and the down-regulation of GlyT1 in the lumbar dorsal horn.

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Section: Discussionsupporting

confidence: 76%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Blockade of Glycine Transporter (GlyT) 2, but Not GlyT1, Ameliorates Dynamic and Static Mechanical Allodynia in Mice With Herpetic or Postherpetic Pain

2010

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“…The authors conclude that blocking glial and/or neuronal glycine transporters increased the level of glycine in the spinal cord, which in turn prolonged the duration of the glycinergic synaptic current. An increase in extracellular glycine without accompanying citrulline release was demonstrated by microdialysis perfusion with ORG25543 of the lumbar dorsal spinal cord of rats (Whitehead et al, 2004). Evidence suggests that the pharmacological blockade of GlyT2 increases either glycinergic and/or GABAergic neurotransmission in vivo in the spinal cord.…”

Section: Discussionmentioning

confidence: 96%

“…The observations that the potency of the antiallodynia effect of high dosages of ORG25935 decreased and the period of the antiallodynia effect by GlyT1 knockdown was shorter than that of GlyT2 knockdown also suggest a counteracting effect by the stimulation of NMDA receptors in the spinal cord and higher brain regions at higher doses of GlyT1 inhibitors, although the time-dependent changes of GlyT1 protein expression were similar to those of GlyT2. In fact, microdialysis perfusion of the lumbar dorsal spinal cord of rats reveals that ORG24598, a selective inhibitor of GlyT1, increases extracellular glycine accompanied by a progressive increase in citrulline, which resulted from activation of the NMDA receptor/nitric oxide synthase signaling cascade (Whitehead et al, 2004). GlyT1 is distributed widely in the central nervous system and may have a role in controlling concentrations of glycine in the vicinity of NMDA receptors.…”

Section: Discussionmentioning

confidence: 99%

Spinal Antiallodynia Action of Glycine Transporter Inhibitors in Neuropathic Pain Models in Mice

Morita¹,

Motoyama²,

Kitayama³

et al. 2008

J Pharmacol Exp Ther

115

143

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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,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 ␣3. 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.Neuropathic pain arising from peripheral or spinal nerve injury and diabetes or infection with herpes virus is a result of the final product of an altered peripheral, spinal, and supraspinal process for which the usual analgesics are not effective and novel analgesics are desired. Recent progress of research on the underlying mechanism of the pathology revealed more complexity, depending on the cause and stage of ongoing neuropathy. Among various mechanisms involved in the pathology, alterations of synaptic transmission within the spinal cord dorsal horn as well as peripheral nerves after peripheral nerve injury play key roles. In addition to the activation of stimulatory spinal neurotransmission, disinhibition of inhibitory neurotransmission has been implicated in the generation of inflammatory and neuropathic pain (Woolf and Mannion, 1999). Glycine as well as GABA serve as major inhibitory neurotransmitters in the spinal cord of vertebrates. In fact, relief from glycinergic inhibition by an inhib-

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Glycine transporters and synaptic function

Zafra

Giménez

2008

IUBMB Life

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SummaryGlycine is an inhibitory neurotransmitter that is mainly active in the caudal areas of the CNS. However, glycine also participates in excitatory neurotransmission since it is a co-agonist of the NMDA subtype of glutamate receptors. The concentration of glycine at synapses is mainly controlled by two sodium and chloride dependent transporters, GLYT1 and GLYT2, proteins that display a complementary distribution and activity in the nervous system. Our understanding of the physiological role of these transporters has advanced recently, thanks to the development of specific inhibitors and the generation of mice defective in the corresponding genes. In addition, the three-dimensional resolution of the structure of a bacterial homologue has shed light on the mechanisms of glycine transport. It is likely that this knowledge will prove to be useful for the development of drugs with antipsychotic, procognitive or analgesic properties. IUBMBIUBMB Life, 60(12): 810-817, 2008

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Positive N-methyl-d-aspartate receptor modulation by selective glycine transporter-1 inhibition in the rat dorsal spinal cord in vivo

Cited by 39 publications

References 57 publications

Blockade of Glycine Transporter (GlyT) 2, but Not GlyT1, Ameliorates Dynamic and Static Mechanical Allodynia in Mice With Herpetic or Postherpetic Pain

Blockade of Glycine Transporter (GlyT) 2, but Not GlyT1, Ameliorates Dynamic and Static Mechanical Allodynia in Mice With Herpetic or Postherpetic Pain

Spinal Antiallodynia Action of Glycine Transporter Inhibitors in Neuropathic Pain Models in Mice

Glycine transporters and synaptic function

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