Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030193 (pain)
 261,466 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Advances in our basic understanding of inhibitory and excitatory amino acid neurotransmission have provided the foundation for directed drug discovery programs to modulate inhibitory GABAergic and excitatory N-methyl-D-aspartate (NMDA) receptor-mediated synapses. Gamma-Amino butyric acid (GABA(A)) and NMDA receptors are complex ion channels formed by multiple protein subunits that act as binding sites for transmitter amino acids and as allosteric regulatory binding sites to regulate ion channel activity. In the case of the NMDA receptor complex, one such allosteric site binds the obligatory glycine and/or d-serine co-agonist. Historical data from preclinical and clinical studies of GABAergic agents have clearly demonstrated that direct receptor modulators lack sufficient therapeutic indices to warrant clinical utility. However, pharmacological modulation of allosteric sites of the GABA multimeric receptor has resulted in the clinical development of safe and efficacious agents, exemplified by the benzodiazepines. Research has also revealed a similar outcome for the NMDA receptor, with allosteric modulators demonstrating improved safety profiles in the modulation of excitatory amino acid (EAA) transmission compared with direct NMDA receptor antagonists. First-generation EAA drugs were low affinity channel blockers of the NMDA multimeric receptor complex and included the anesthetic agent ketamine and the Alzheimer's drug memantine. As predicted by preclinical studies, direct NMDA receptor antagonists (eg, selfotel (Novartis AG) and high-affinity channel blockers (eg, dizocilpine) failed in the clinic as a result of narrow therapeutic indices. More recent efforts have focused on glycine/d-serine co-agonist function. These approaches include partial glycine agonists, in their agonist dose-range, for cognitive improvement and for treating schizophrenia. Such partial glycine agonists are also being advanced for the treatment of neuropathic pain in the antagonist dose range. An alternate approach to partial glycine agonists is to inhibit the uptake carrier(s) for glycine (ie, GlyT-1 and GlyT-2), thereby potentiating the lifetime of synaptic glycine. A number of glycine uptake inhibitors have been reported and their preclinical profiles support investigation into their utility in treating schizophrenia.
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PMID:The NMDA receptor complex: a long and winding road to therapeutics. 1577 95

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.
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PMID:Spinal antiallodynia action of glycine transporter inhibitors in neuropathic pain models in mice. 1844 67

Gliosis is strongly implicated in the development and maintenance of persistent pain states following chronic constriction injury of the sciatic nerve. Here we demonstrate that in the dorsal horn of the spinal cord, gliosis is accompanied by changes in glial amino acid transporters examined by immunoblot, immunohistochemistry and RT-PCR. Cytokines, proinflammatory mediators and microglia increase up to postoperative day (pd) 3 before decreasing on pd 7. Then, spinal glial fibrillary acidic protein increases on pd 7, lasting until pd 14 and later. Simultaneously, the expression of glial amino acid transporters for glycine and glutamate (GlyT1 and GLT1) is reduced on pd 7 and pd 14. Consistent with a reduced expression of GlyT1 and GLT1, high performance liquid chromatography reveals a net increase in the concentration of glutamate and glycine on pd 7 and pd 14 in tissue from the lumbar spinal cord of neuropathic mice. In this study we have confirmed that microglial activation precedes astrogliosis. Such a glial cytoskeletal rearrangement correlates with a marked decrease in glycine and glutamate transporters, which might, in turn, be responsible for the increased concentration of these neurotransmitters in the spinal cord. We speculate that these phenomena might contribute, via over-stimulation of NMDA receptors, to the changes in synaptic functioning that are responsible for the maintenance of persistent pain.
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PMID:Gliosis alters expression and uptake of spinal glial amino acid transporters in a mouse neuropathic pain model. 1863 71

Changes in glycinergic neurotransmission in the spinal cord dorsal horn are critically involved in the development of pathological pain. Since the concentration of glycine in the synaptic cleft is controlled by specialized proteins, the glycine transporters GlyT1 and GlyT2, manipulation of this system might have significant effects on nociception. In the present study, we investigated the effects of the spinally applied glycine transporter inhibitors ALX 5407 (GlyT1) and ALX 1393 (GlyT2) on nociceptive behavior in the chronic constriction injury model of neuropathic pain in male Wistar rats. After implementation of neuropathy, the animals were injected with three dosages of ALX 5407 and ALX 1393 (10, 50 and 100 microg) via an intrathecal catheter (n = 8 each). Subsequently, nociceptive behavior was evaluated regarding thermal hyperalgesia (Hargreaves method) and mechanical sensitization (von Frey filaments) over 240 min after application. Inhibition of GlyT1 by ALX 5407 had differential dose-dependent effects. While the highest and the lowest concentrations were antinociceptive, the medium dose evoked pronociceptive effects. The GlyT2 inhibitor ALX 1393 was only effective in the highest concentration at which it exerted significant antinociception. However, in the same dose, ALX 1393 caused remarkable side effects such as respiratory depression and motor deficits in three animals. Our findings indicate that inhibition of glycine transporters is capable of evoking significant effects on nociceptive behavior in neuropathic pain. Whether glycine transporter inhibitors have the capability to gain clinical relevance as analgesic compounds on the long run has to be elucidated in further investigations.
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PMID:Differential effects of spinally applied glycine transporter inhibitors on nociception in a rat model of neuropathic pain. 1879 97

Injury to peripheral or spinal nerves following either trauma or disease has several consequences including the development of neuropathic pain. This syndrome is often refractory against conventional analgesics; and thus, novel medicaments are desired for its treatment. Recent studies have emphasized that dysfunction of inhibitory neuronal regulation of pain signal transduction may be relevant to the development of neuropathic pain. Glycinergic neurons are localized in specific brain regions and the spinal cord, where they play an important role in the prevention of pathological pain symptoms. Thus, an enhancement of glycinergic control in the spinal cord is a promising strategy for pain relief from neuropathic pain. Glycine transporter (GlyT) 1 and GlyT2, which are located in glial cells and neurons, respectively play important roles by clearing synaptically released glycine or supplying glycine to glycinergic neurons to regulate glycinergic neurotransmission. Thus, an inhibition of GlyTs could be used to modify pain signal transmission in the spinal cord. Recently developed specific inhibitors of GlyTs have made this possibility a reality. Both GlyT1 and GlyT2 inhibitors produced potential anti-nociceptive effect in various neuropathic pain models, chronic and acute inflammatory models in animals. Their anti-allodynia effects are mediated by the inhibition of GlyTs following activation of spinal glycine receptor alpha3. These results established GlyTs as target molecules for medicaments for neuropathic pain. Moreover, the phase-dependent anti-allodynia effects of GlyT inhibitors have provided important information on effective therapeutic strategies and also understanding the underlying molecular mechanisms of the development of neuropathic pain.
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PMID:Glycine transporter inhibitors as a novel drug discovery strategy for neuropathic pain. 1939 90

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 alpha1-subunit mRNA was decreased in the lumbar dorsal horn at the herpetic, but not postherpetic stage, without alteration in alpha3-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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PMID:Blockade of glycine transporter (GlyT) 2, but not GlyT1, ameliorates dynamic and static mechanical allodynia in mice with herpetic or postherpetic pain. 2017 9

Inhibition mediated by glycine and GABA in the spinal cord dorsal horn is essential for controlling sensitivity to painful stimuli. Loss of inhibition results in hyperalgesia, a sensitized response to a painful stimulus, and allodynia, a pain-like response to an innocuous stimulus like touch. The latter is due, in part, to disinhibition of an excitatory polysynaptic pathway linking low threshold touch input to pain projection neurons. This critical impact of disinhibition raises the issue of what regulates the activity of inhibitory interneurons in the dorsal horn under non-pathological conditions. We have found that inhibitory neurons throughout lamina I-III, identified by the GAD67 promoter-driven EGFP, are tonically inhibited by glycine or GABA in a regionally distinct way that is mirrored by their inhibitory synaptic input. This tonic inhibition strongly modifies action potential firing properties. Surprisingly, we found that inhibitory neurons at the lamina II/III border are under tonic glycinergic control and receive synapses that are predominantly glycinergic. Futhermore, this tonic glycinergic inhibition remains strong as the mice mature postnatally. Interestingly, GlyT1, the glial glycine transporter, regulates the strength of tonic glycinergic inhibition of these glycine-dominant neurons. The more dorsal lamina I and IIo inhibitory neurons are mainly under control by tonic GABA action and receive synapses that are predominantly GABAergic. Our work supports the hypothesis that tonic glycine inhibition controls the inhibitory circuitry deep in lamina II that is likely to be responsible for separating low threshold input from high threshold output neurons of lamina I.
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PMID:Glycinergic and GABAergic tonic inhibition fine tune inhibitory control in regionally distinct subpopulations of dorsal horn neurons. 2049 32

Glycine transporter inhibitors modulate the transmission of pain signals. Since it is well known that extracts from medicinal plants such as Chelidonium majus exhibit analgesic properties, we investigated the effects of alkaloids typically present in this plant on glycine transporters. We found that chelerythrine and sanguinarine selectively inhibit the glycine transporter GlyT1 with comparable potency in the low micromolar range while berberine shows no inhibition at all. At this concentration both alkaloids only minimally affected transport of the closely related glycine transporter GlyT2, suggesting that the effect is not mediated by the inhibitory activity of these alkaloids on the Na(+)/K(+) ATPase. GlyT1 inhibition was time-dependent, noncompetitive and increased with glycine concentration. While chelerythrine inhibition was reversible, the effect of sanguinarine was resistant to wash out. These results suggest that benzophenanthridine alkaloids interact with glycine transporters and at low micromolar range selectively target glycine transporter GlyT1.
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PMID:Differential effect of the benzophenanthridine alkaloids sanguinarine and chelerythrine on glycine transporters. 2131 25

Peptidomimetics hold a great promise as therapeutic agents for neurodegenerative disorders. We previously described a Nerve Growth Factor (NGF)-like peptide, now named BB14, which was found to act as a strong TrkA agonist and to be effective in the sciatic nerve injury model of neuropathic pain. In this report we present the effects of BB14 in reducing reactive astrocytosis and reverting neuroplastic changes of the glutamate/GABAergic circuitry in the lumbar spinal cord following spared nerve injury (SNI) of the sciatic nerve. Immunohistochemical analysis of spinal cord sections revealed that SNI was associated with increased microglial (Iba1) and astrocytic (GFAP) responses, indicative of reactive gliosis. These changes were paralleled by (i) decreased glial aminoacid transporters (GLT1 and GlyT1) and increased levels of (ii) neuronal glutamate transporter EAAC1, (iii) neuronal vesicular GABA transporter (vGAT) and (iv) the GABAergic neuron marker GAD65/67. A remarkable increase of the Glutamate/GABA ratio and the reduction of glutathione (GSH) levels were also indicative of modifications of glial function in neuroprotection. All these molecular changes were found to be linked to an alteration of endogenous NGF metabolism, as demonstrated by decreased levels of mature NGF, increase of proNGF and increased activity of NGF-degrading methallo-proteinases (MMPs). Biochemical alterations and SNI-related neuropathic behavior, characterized by allodynia and hyperalgesia, were reversed by 7-days i.t. administration of the NGF-like peptide BB14, as well as by increasing endogenous NGF levels by i.t. infusion of GM6001, a MMPs inhibitor. All together, while confirming the correlation between reactive astrogliosis and perturbation of synaptic circuitry in the SNI model of peripheral nerve injury, these data strongly support the beneficial effect of BB14 in reducing reactive astrogliosis and restoring synaptic homeostasis under pathological conditions linked to alteration of NGF availability and signaling, thereby suggesting a potential role of BB14 as a therapeutic agent.
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PMID:BB14, a Nerve Growth Factor (NGF)-like peptide shown to be effective in reducing reactive astrogliosis and restoring synaptic homeostasis in a rat model of peripheral nerve injury. 2162 Sep 45

Glycine plays a key role in regulating inhibitory neurotransmission in the spinal cord and concentrations of glycine in the CNS are regulated by two subtypes of high affinity glycine transporters, GlyT1 and GlyT2. In this mini review we will discuss a series of lipid inhibitors of GlyT2 that show promise as analgesics in the treatment of neuropathic and inflammatory pain. N-arachidonyl-glycine inhibits the rate of transport by GlyT2, but has very little or no activity on GlyT1. We will discuss structure-activity studies of the actions of related lipids on GlyT2 and also the characterization of a more potent lipid inhibitor of GlyT2, oleoyl-l-carnitine. Both N-arachidonyl-glycine and oleoyl-l-carnitine show specificity for GlyT2 over GlyT1, which has allowed the use of chimeric GlyT1/GlyT2 transporters to begin characterizing the molecular basis for specificity and mechanism of action of these lipid inhibitors. Although our understanding of the molecular basis for lipid inhibition is still in its infancy, it appears that extracellular loop 4 of GlyT2 plays an important role in the inhibitory mechanism.
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PMID:Lipid inhibitors of high affinity glycine transporters: identification of a novel class of analgesics. 2403 83


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