The Antinociceptive Effect of Intrathecal Administration of Glycine Transporter-2 Inhibitor ALX1393 in a Rat Acute Pain Model

Haranishi, Yasunori; Hara, Koji; Terada, Tadanori; Nakamura, Seiya; Sata, Takeyoshi

doi:10.1213/ane.0b013e3181c7ebbb

Cited by 50 publications

(49 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Therefore, it has been reported that manipulation of the synaptic glycine concentrations affects nociception by influencing both excitatory and inhibitory transmission. Pharmacological blockade of GLYT2 in the spinal cord increases glycinergic neurotransmission in vivo and produces pain relief in rat acute pain models (28) and neuropathic pain models (25,27,29,30). However, inhibition of GLYT1 can enhance both excitatory and inhibitory transmission, and its pharmacological blockade may evoke anti-or pro-nociceptive effects in mouse pain models (25-27, 29, 30).…”

Section: Discussionmentioning

confidence: 99%

“…A loss of GABAergic and glycinergic synaptic inhibition in this region has been recognized as an important process in the development and maintenance of chronic pain (23,24). Pharmacological blockade of glycine transporters in the spinal cord increases either glycinergic and/or GABAergic neurotransmission in vivo and produces pain relief in mouse pain models (25)(26)(27)(28)(29)(30). This suggests that glycine transport can modulate the function of glycinergic dorsal horn neurons.…”

mentioning

confidence: 99%

See 1 more Smart Citation

P2Y Purinergic Regulation of the Glycine Neurotransmitter Transporters

Jiménez

Zafra

Pérez-Sen

et al. 2011

Journal of Biological Chemistry

View full text Add to dashboard Cite

The sodium-and chloride-coupled glycine neurotransmitter transporters (GLYTs) control the availability of glycine at glycine-mediated synapses. The mainly glial GLYT1 is the key regulator of the glycine levels in glycinergic and glutamatergic pathways, whereas the neuronal GLYT2 is involved in the recycling of synaptic glycine from the inhibitory synaptic cleft. In this study, we report that stimulation of P2Y purinergic receptors with 2-methylthioadenosine 5 -diphosphate in rat brainstem/spinal cord primary neuronal cultures and adult rat synaptosomes leads to the inhibition of GLYT2 and the stimulation of GLYT1 by a paracrine regulation. These effects are mainly mediated by the ADP-preferring subtypes P2Y 1 and P2Y 13 because the effects are partially reversed by the specific antagonists N 6 -methyl-2 -deoxyadenosine-3 ,5 -bisphosphate and pyridoxal-5 -phosphate-6-azo(2-chloro-5-nitrophenyl)-2,4-disulfonate and are totally blocked by suramin. P2Y 12 receptor is additionally involved in GLYT1 stimulation. Using pharmacological approaches and siRNAmediated protein knockdown methodology, we elucidate the molecular mechanisms of GLYT regulation. Modulation takes place through a signaling cascade involving phospholipase C activation, inositol 1,4,5-trisphosphate production, intracellular Ca 2؉ mobilization, protein kinase C stimulation, nitric oxide formation, cyclic guanosine monophosphate production, and protein kinase G-I (PKG-I) activation. GLYT1 and GLYT2 are differentially sensitive to NO/cGMP/PKG-I both in brain-derived preparations and in heterologous systems expressing the recombinant transporters and P2Y 1 receptor. Sensitivity to 2-methylthioadenosine 5 -diphosphate by GLYT1 and GLYT2 was abolished by small interfering RNA (siRNA)-mediated knockdown of nitric-oxide synthase. Our data may help define the role of GLYTs in nociception and pain sensitization.

show abstract

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

P2Y Purinergic Regulation of the Glycine Neurotransmitter Transporters

Jiménez

Zafra

Pérez-Sen

et al. 2011

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…The observation that GlyT2 inhibitors have a similar outcome rather suggests that a moderate inhibition of GlyT2 might increase synaptic level of glycine without a significant effect on its quantal release. This seems to be the case of ALX-1393, one of the best characterized GlyT2 inhibitors in vivo [73][74][75][76][77][78][79][80]. Intrathecal injection of ALX-1393 inhibits acute thermal and mechanical pain responses and is especially active in reversing sensitized responses, reducing mechanical allodynia in neuropathic and inflammatory pain models.…”

Section: Sensory Dysfunctions: Neurogenic and Inflammatory Painmentioning

confidence: 99%

Glycinergic transmission: glycine transporter GlyT2 in neuronal pathologies

2016

View full text Add to dashboard Cite

Glycinergic neurons are major contributors to the regulation of neuronal excitability, mainly in caudal areas of the nervous system. These neurons control fluxes of sensory information between the periphery and the CNS and diverse motor activities like locomotion, respiration or vocalization. The phenotype of a glycinergic neuron is determined by the expression of at least two proteins: GlyT2, a plasma membrane transporter of glycine, and VIAAT, a vesicular transporter shared by glycine and GABA. In this article, we review recent advances in understanding the role of GlyT2 in the pathophysiology of inhibitory glycinergic neurotransmission. GlyT2 mutations are associated to decreased glycinergic function that results in a rare movement disease termed hyperekplexia (HPX) or startle disease. In addition, glycinergic neurons control pain transmission in the dorsal spinal cord and their function is reduced in chronic pain states. A moderate inhibition of GlyT2 may potentiate glycinergic inhibition and constitutes an attractive target for pharmacological intervention against these devastating conditions.

show abstract

“…Associated with DN, assessment of altered responses to both nociceptive and non-nociceptive stimuli in diabetic rats and mice is performed using a number of behavioural tests, among which paw withdrawal, tail flick, hot-plate and cold-plate are the most widely used. In general, tail-immersion test at spinal level; hot-plate test at both spinal and supraspinal level and cold-plate test through peripheral sensitization give an idea to evaluate the pain perception and transmission (25,26).…”

Section: Discussionmentioning

confidence: 99%

Evaluation of the Effects of Novel Nafimidone Derivatives on Thermal Hypoalgesia in Mice with Diabetic Neuropathy

et al. 2013

View full text Add to dashboard Cite

The worldwide diabetes epidemic has shown no signs of abatement. Its prevalence has more than doubled since 1980 (1). Diabetic neuropathy (DN) is the most common diabetic complication, afflicting over 50% of all diabetics. The possible biochemical pathomechanisms include oxidative stress, activation of the polyol pathway, increased advanced glycation end products (AGEs) and their receptors, impaired ionic homeostasis of cells and activation of protein kinases (PKC and PKA), and mitogen-activated protein kinases (MAPK), and inducible nitric oxide synthase (2-6).Understanding the biochemical mechanisms underlying diabetic neuropathic pain and sensory disorders requires preclinical studies in animal models. The streptozotocin (STZ)-induced diabetic rodent is the most commonly used animal model of diabetes (7,8). On the other hand, existing animal models of diabetic painful and insensate neuropathy, however, have serious limitations. Diabetic rats and mice have limited life span and rarely show evidence of overt neuropathy, such as demyelination, axonal degeneration, fiber loss, or axonal regeneration in their peripheral nerves. This makes diabetic rodents unsuitable for studying the contribution of these phenomena of DN to pain or to loss of sensory function (9). Nonetheless, despite these limitations, assessment of behavioral responses to external stimuli in diabetic rats and mice (i.e., thermal and mechanical hyper and hypoalgesia, tactile allodynia, as well as formalin-induced spontaneous nociceptive behavior) has led to identification of a number of mechanisms of loss of sensation and/or pain in diabetes (10).Decades of research elucidating the pathophysiology of diabetic neuropathy have failed, thus far, to produce a treatment that prevents or reverses its development and progression. Recently, however, numerous competing or parallel pathological pathways have begun to intersect and complement each other, illuminating potential pharmacologic targets. The current foci of diabetic neuropathy research are excessive activation of sodium channels and corrupted molecular mechanisms of cellular pathways of related kinases (11).Voltage-gated sodium channels (Na v Chs) are a necessary component of normal sensation, emotions, thoughts and movements and are of particular interest as target for neuro- ABSTRACTObjective: Diabetic neuropathy (DN) is a common complication in Diabetes Mellitus. The streptozotocin-induced diabetic rodent is the most commonly used animal model of diabetes and increased sodium channel expression and activity were revealed in this model. At this study, we evaluated the effect of three different nafimidone derivatives which have possible anticonvulsant activity on disorders of thermal pain sensation in diabetic mice.Study Design: Randomized animal experiment.Material and Methods: Mice were divided randomly into five groups (5 mice per group): Control, Diabetes, Dibetes+C1, Diabetes+C2, Diabetes+C3. We used hot and cold plate, and tail-immersion tests for assessment of thermal nociceptive response...

show abstract

The Antinociceptive Effect of Intrathecal Administration of Glycine Transporter-2 Inhibitor ALX1393 in a Rat Acute Pain Model

Abstract: This study demonstrates the antinociceptive action of ALX1393 on acute pain. These findings suggest that the inhibitory neurotransmitter transporters are promising targets for the treatment of acute pain and that the selective inhibitor of GlyT2 could be a novel therapeutic drug.

Cited by 50 publications

References 26 publications

P2Y Purinergic Regulation of the Glycine Neurotransmitter Transporters

P2Y Purinergic Regulation of the Glycine Neurotransmitter Transporters

Glycinergic transmission: glycine transporter GlyT2 in neuronal pathologies

Evaluation of the Effects of Novel Nafimidone Derivatives on Thermal Hypoalgesia in Mice with Diabetic Neuropathy

Contact Info

Product

Resources

About