Articles: hyperalgesia.
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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.
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Dysfunction of GABAergic inhibitory controls contributes to the development of neuropathic pain. We examined our hypotheses that (1) chronic constriction injury (CCI)-induced neuropathic pain is associated with increased spinal GABAergic neuron apoptosis, and (2) hyperbaric oxygen therapy (HBO) alleviates CCI-induced neuropathic pain by inhibiting GABAergic neuron apoptosis. ⋯ Increased apoptotic GABAergic neurons induced by activation of key proteins of mitochondrial apoptotic pathways in the dorsal horn of the spinal cord is critical in CCI-induced neuropathic pain. The inhibitory role of HBO in GABAergic neuron apoptosis suppresses ongoing neuropathic pain.
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Journal of anesthesia · Oct 2017
The preventive effects of dexmedetomidine on endotoxin-induced exacerbated post-incisional pain in rats.
Low-grade endotoxin (lipopolysaccharide; LPS) exposure may contribute to the development of exaggerated acute postoperative pain. In the present study, we investigated the possible impact of intraoperative administration of dexmedetomidine (DEX) on LPS-induced postoperative hyperalgesia in a rat incisional pain model. ⋯ Our findings indicate that intraoperative DEX treatment can prevent LPS-induced exacerbated post-incisional pain via the α2-adrenergic receptor signaling pathway.
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The impaired attenuation of pain by the application of a noxious conditioning stimulus at a segmentally distinct site, known as conditioned pain modulation (CPM), has been implicated in clinical pain states. Chronic lateral epicondylalgia (LE), which is characterized by lower pressure pain thresholds (PPTs) at sites remote to the affected elbow and spinal cord hyperexcitability, is a clinical pain state that might plausibly involve less efficacious CPM. This study aimed to determine whether LE exhibits a less efficacious CPM compared with that in pain-free controls. ⋯ The results that suggest an impaired ability to modulate pain might be associated with the previously observed spinal cord hyperexcitability and the mechanical hyperalgesia that characterizes LE.
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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.