Articles: neuralgia.
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Long noncoding RNAs have been implicated in neuropathy. Here, we identify and validate a long noncoding RNA, MRAK009713, as the primary regulator of neuropathic pain in chronic constriction injury (CCI) rats. MRAK009713 expression was markedly increased in CCI rats associated with enhanced pain behaviors, and small interfering RNA against MRAK009713 significantly reduced both mechanical and thermal hyperalgesia in the CCI rats. ⋯ Overexpression of MRAK009713 markedly increased expression of P2X3 in the dorsal root ganglia of the control rats, and MRAK009713 small interfering RNA significantly inhibited the P2X3 expression in the dorsal root ganglia of the CCI rats. MRAK009713 directly interacted with the P2X3 protein heterologously expressed in the human embryonic kidney (HEK) 293 cells and potentiated P2X3 receptor function. Thus, MRAK009713 is a novel positive regulator of neuropathic pain in rats through regulating the expression and function of the P2X3 receptor.
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Randomized Controlled Trial
Randomized, double-blind, placebo-controlled, dose-escalation study: Investigation of the safety, pharmacokinetics, and antihyperalgesic activity of l-4-chlorokynurenine in healthy volunteers.
Neuropathic pain is a significant medical problem needing more effective treatments with fewer side effects. Overactive glutamatergic transmission via N-methyl-d-aspartate receptors (NMDARs) are known to play a role in central sensitization and neuropathic pain. Although ketamine, a NMDAR channel-blocking antagonist, is often used for neuropathic pain, its side-effect profile and abusive potential has prompted the search for a safer effective oral analgesic. A novel oral prodrug, AV-101 (l-4 chlorokynurenine), which, in the brain, is converted into one of the most potent and selective GlyB site antagonists of the NMDAR, has been demonstrated to be active in animal models of neuropathic pain. The two Phase 1 studies reported herein were designed to assess the safety and pharmacokinetics of AV-101, over a wide dose range, after daily dosing for 14-days. As secondary endpoints, AV-101 was evaluated in the capsaicin-induced pain model. ⋯ This article presents the safety and PK of AV-101, a novel oral prodrug producing a potent and selective GlyB site antagonist of the NMDA receptor. These data indicate that AV-101 has excellent safety and PK characteristics providing support for advancing AV-101 into Phase 2 studies in neuropathic pain, and even provides data suggesting that AV-101 may have a role in treating depression.
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Review Meta Analysis
Repetitive transcranial magnetic stimulation for pain after spinal cord injury: a systematic review and meta-analysis.
The evidence regarding efficiency of repetitive transcranial magnetic stimulation (rTMS) on relief of neuropathic pain (NP) in patients with prior spinal cord injury (SCI) is controversial. The current meta-analysis aimed to assess the efficacy of rTMS in pain relieve in patients suffering from SCI associated NP. ⋯ rTMS might reduce SCI associated neuropathic pain; however, further studies are required to support our conclusions.
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Multicenter Study Observational Study
Capsaicin 8% Patch Repeat Treatment in Nondiabetic Peripheral Neuropathic Pain: A 52-Week, Open-Label, Single-Arm, Safety Study.
To investigate the long-term safety and tolerability of capsaicin 8% patch repeat treatment in nondiabetic patients with peripheral neuropathic pain. ⋯ Generally, capsaicin 8% patch repeat treatment over 52 weeks was well tolerated, with variable alteration in sensory function and minimal chance of complete sensory loss.
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Eur. J. Clin. Pharmacol. · Oct 2017
ReviewChallenges in translational drug research in neuropathic and inflammatory pain: the prerequisites for a new paradigm.
Despite an improved understanding of the molecular mechanisms of nociception, existing analgesic drugs remain limited in terms of efficacy in chronic conditions, such as neuropathic pain. Here, we explore the underlying pathophysiological mechanisms of neuropathic and inflammatory pain and discuss the prerequisites and opportunities to reduce attrition and high-failure rate in the development of analgesic drugs. ⋯ A different paradigm is required for the identification of relevant targets and candidate molecules whereby pain is coupled to the cause of sensorial signal processing dysfunction rather than clinical symptoms. Biomarkers which enable the characterisation of drug binding and target activity are needed for a more robust dose rationale in early clinical development. Such an approach may be facilitated by quantitative clinical pharmacology and evolving technologies in brain imaging, allowing accurate assessment of target engagement, and prediction of treatment effects before embarking on large clinical trials.