pyrimidinones has been researched along with Neuralgia* in 6 studies
6 other study(ies) available for pyrimidinones and Neuralgia
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CXCR3 contributes to neuropathic pain via ERK activation in the anterior cingulate cortex.
The anterior cingulate cortex (ACC) is activated by noxious stimuli and is involved in the affective component of pain processing; but its role in the sensory component of pain remains largely unknown. Studies have verified that Chemokine (C-X-C motif) receptor 3 (CXCR3) is involved in nociceptive sensitization in the spinal cord after peripheral nerve injury; however, the expression of CXCR3 in the ACC and its role in neuropathic pain has not been reported. Here, we showed that CXCR3 co-localized with neurons in the ACC and the upregulation of CXCR3 corresponded with hypersensitive behaviors after a chronic constriction injury of the sciatic nerve. Pharmacological blockade of CXCR3 using local injection of its inhibitor, AMG487, into the ACC significantly attenuated hyperalgesia induced by chronic constriction injury and suppressed the phosphorylation of extracellular signal-regulated kinase (ERK). Collectively, these results suggest that CXCR3 in the ACC is involved in hyperalgesia induced by peripheral nerve injury and ERK may be a downstream target. Topics: Acetamides; Animals; Behavior, Animal; Constriction, Pathologic; Enzyme Activation; Extracellular Signal-Regulated MAP Kinases; Gyrus Cinguli; Hyperalgesia; Male; Neuralgia; Phosphorylation; Pyrimidinones; Rats, Sprague-Dawley; Receptors, CXCR3; Up-Regulation | 2020 |
Icilin reduces voltage-gated calcium channel currents in naïve and injured DRG neurons in the rat spinal nerve ligation model.
Recently, the transient receptor potential (TRP) channels TRPM8 and TRPA1 have been identified as molecular sensors for cold, and it has been suggested that they play a crucial role in allodynia by modulating voltage-gated calcium channel currents (ICa(V)). The aim of this study was to analyze the modulation of ICa(V) by the TRPM8-agonist icilin in vitro and to investigate the analgesic effect of icilin in a neuropathic pain model in vivo. Whole cell patch-clamp recordings were performed on isolated naïve and injured rat dorsal root ganglia (DRG) neurons, and the analgesic efficacy of icilin applied topically to the paws or intrathecally was tested in rats after spinal nerve ligation (SNL). ICa(V) (depolarization from -80 to 0mV) in naïve DRG neurons was reduced dose dependently (0.002-200µM) by icilin (18-80%). Subtype isolation of calcium channels show a marked reduction of L-type channel currents compared to N-type channel currents. The effects of icilin on ICa(V) were not significantly different in non-injured and SNL-injured DRG neurons. In vivo, neither topical (10-200µM) nor intrathecal application of icilin (0.1nM to 1µM) affected tactile allodynia or thermal hyperalgesia after SNL, but it increases cold allodynia 6h after application. We conclude that the icilin-induced modulation of ICa(V) in DRG neurons is unlikely to mediate analgesic effects or contribute directly to the pathogenesis of cold allodynia in the rat SNL model, but it is a potential mechanism for the analgesic effects of icilin in other pain models. Topics: Animals; Calcium Channel Blockers; Calcium Channels, L-Type; Calcium Channels, N-Type; Cells, Cultured; Cold Temperature; Disease Models, Animal; Dose-Response Relationship, Drug; Ganglia, Spinal; Hyperalgesia; Ligation; Male; Membrane Potentials; Neuralgia; Neurons; Patch-Clamp Techniques; Peripheral Nerve Injuries; Pyrimidinones; Rats; Rats, Wistar; Spinal Nerves; TRPM Cation Channels | 2014 |
Modulation of K(v)7 potassium channels by a novel opener pyrazolo[1,5-a]pyrimidin-7(4H)-one compound QO-58.
Modulation of K(v)7/M channel function represents a relatively new strategy to treat neuronal excitability disorders such as epilepsy and neuropathic pain. We designed and synthesized a novel series of pyrazolo[1,5-a] pyrimidin-7(4H)-one compounds, which activate K(v)7 channels. Here, we characterized the effects of the lead compound, QO-58, on K(v)7 channels and investigated its mechanism of action.. A perforated whole-cell patch technique was used to record K(v)7 currents expressed in mammalian cell lines and M-type currents from rat dorsal root ganglion neurons. The effects of QO-58 in a rat model of neuropathic pain, chronic constriction injury (CCI) of the sciatic nerve, were also examined.. QO-58 increased the current amplitudes, shifted the voltage-dependent activation curve in a more negative direction and slowed the deactivation of K(v)7.2/K(v)7.3 currents. QO-58 activated K(v)7.1, K(v)7.2, K(v)7.4 and K(v)7.3/K(v)7.5 channels with a more selective effect on K(v)7.2 and K(v)7.4, but little effect on K(v)7.3. The mechanism of QO-58's activation of K(v)7 channels was clearly distinct from that used by retigabine. A chain of amino acids, Val(224)Val(225)Tyr(226), in K(v)7.2 was important for QO-58 activation of this channel. QO-58 enhanced native neuronal M currents, resulting in depression of evoked action potentials. QO-58 also elevated the pain threshold of neuropathic pain in the sciatic nerve CCI model.. The results indicate that QO-58 is a potent modulator of K(v)7 channels with a mechanism of action different from those of known K(v)7 openers. Hence, QO-58 shows potential as a treatment for diseases associated with neuronal hyperexcitability. Topics: Action Potentials; Animals; CHO Cells; Cricetinae; Cricetulus; Dose-Response Relationship, Drug; Humans; Ion Channel Gating; KCNQ2 Potassium Channel; KCNQ3 Potassium Channel; Molecular Structure; Neuralgia; Neurons; Patch-Clamp Techniques; Pyrazoles; Pyrimidines; Pyrimidinones; Rats; Rats, Sprague-Dawley; Structure-Activity Relationship; Transfection | 2013 |
Clinical features of adverse reactions associated with telbivudine.
To analyze the clinical features and risk factors of adverse reactions associated with telbivudine.. Clinical data were collected from cases that presented with serious adverse reactions to telbivudine. We analyzed general information and medicine status, clinical features, results of examination, and misdiagnosis.. Out of 105 patients who were treated with telbivudine for hepatitis B in an outpatient department from January, 2007 to January, 2008, five presented with serious adverse drug reactions. Most of these five patients had used other nucleoside analogues in the past. Four were treated with a combination of telbivudine and interferon or another nucleoside analogue, while the other received an increased dose of telbivudine. The main adverse reactions were myalgia and general weakness. This was accompanied by cardiac arrhythmia in one patient, and nervous symptoms in three. Serum creatine kinase was elevated. The rate of misdiagnosis was high.. The adverse reactions were related to telbivudine, but the biological mechanism of the reactions is not yet clear. Combination therapy with interferon or another nucleoside analogue and a high dose may increase the risk of adverse reactions. Topics: Adult; Arrhythmias, Cardiac; Creatine Kinase; Drug Synergism; Hepatitis B, Chronic; Humans; Interferons; Male; Middle Aged; Muscle Weakness; Neuralgia; Nucleosides; Pyrimidinones; Retrospective Studies; Risk Factors; Telbivudine; Thymidine | 2008 |
Comparison of icilin- and cold-evoked responses of spinal neurones, and their modulation of mechanical activity, in a model of neuropathic pain.
Cold allodynia is a poorly understood symptom of neuropathic pain. Two members of the transient receptor potential (TRP) family of proteins, TRPM8 and TRPA1, may contribute to cold somatosensation. The aim of the present study was to investigate the usefulness of icilin as a pharmacological tool to study primary afferent fibre responses to cold stimuli and to determine whether there are differences in the responses of spinal neurones to cooling of peripheral receptive fields in control versus neuropathic rats. The effects of icilin, a TRPM8 and TRPA1 agonist, on intracellular Ca(2+) ([Ca(2+)](i)) responses of small diameter adult dorsal root ganglia (DRG) neurones were determined. Icilin (10 nM-10 microM) produced a concentration-related increase in [Ca(2+)](i) in DRG neurones, which was attenuated by the non-selective TRP channel antagonist ruthenium red (10 microM). In vivo electrophysiology in naïve, sham-operated and SNL rats demonstrated that application of ice to receptive fields evoked firing of wide dynamic range (WDR) neurones, which was significantly greater in SNL rats than naïve and sham-operated rats. Intraplantar injection of icilin did not evoke firing of WDR neurones in naïve, sham-operated or SNL rats but inhibited mechanically-evoked responses of WDR neurones in naïve and sham-operated rats, whilst facilitating mechanically-evoked responses in SNL rats. Icilin increased both innocuous (sham-operated and SNL rats) and noxious (SNL rats) receptive field sizes of WDR neurones. Our data suggests that icilin modulates the mechanosensitivity of dorsal horn neurones. The differing effects of ice and icilin on dorsal horn neurones indicate different mechanisms of action. Topics: Analysis of Variance; Animals; Ankyrins; Calcium; Calcium Channel Blockers; Calcium Channels; Cells, Cultured; Cold Temperature; Disease Models, Animal; Dose-Response Relationship, Drug; Evoked Potentials; Ganglia, Spinal; Hyperesthesia; Ligation; Male; Mechanoreceptors; Neuralgia; Neurons; Pain Threshold; Pyrimidinones; Rats; Rats, Sprague-Dawley; Spinal Cord; Spinal Nerves; TRPA1 Cation Channel; TRPC Cation Channels; TRPM Cation Channels | 2008 |
Analgesia mediated by the TRPM8 cold receptor in chronic neuropathic pain.
Chronic established pain, especially that following nerve injury, is difficult to treat and represents a largely unmet therapeutic need. New insights are urgently required, and we reasoned that endogenous processes such as cooling-induced analgesia may point the way to novel strategies for intervention. Molecular receptors for cooling have been identified in sensory nerves, and we demonstrate here how activation of one of these, TRPM8, produces profound, mechanistically novel analgesia in chronic pain states.. We show that activation of TRPM8 in a subpopulation of sensory afferents (by either cutaneous or intrathecal application of specific pharmacological agents or by modest cooling) elicits analgesia in neuropathic and other chronic pain models in rats, thereby inhibiting the characteristic sensitization of dorsal-horn neurons and behavioral-reflex facilitation. TRPM8 expression was increased in a subset of sensory neurons after nerve injury. The essential role of TRPM8 in suppression of sensitized pain responses was corroborated by specific knockdown of its expression after intrathecal application of an antisense oligonucleotide. We further show that the analgesic effect of TRPM8 activation is centrally mediated and relies on Group II/III metabotropic glutamate receptors (mGluRs), but not opioid receptors. We propose a scheme in which Group II/III mGluRs would respond to glutamate released from TRPM8-containing afferents to exert an inhibitory gate control over nociceptive inputs.. TRPM8 and its central downstream mediators, as elements of endogenous-cooling-induced analgesia, represent a novel analgesic axis that can be exploited in chronic sensitized pain states. Topics: Acrolein; Amino Acids; Analgesia; Analysis of Variance; Animals; Blotting, Western; Cold Temperature; Dose-Response Relationship, Drug; Electrophysiology; Immunohistochemistry; Male; Menthol; Neuralgia; Oligonucleotides, Antisense; Pyrimidinones; Rats; Rats, Wistar; Receptors, Glutamate; Reflex; TRPM Cation Channels; Xanthenes | 2006 |