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Diabetes mellitus (DM) is a major global health concern, affecting more than 9% of the world population. The most common complication of DM is diabetic peripheral neuropathy (DPN), which leads to neuropathic pain in as many as 50% of patients. Despite its prevalence, there is neither good prevention of nor treatments for DPN, representing a major gap in care for the many who are afflicted. It has long been known from patient studies that both small and large primary afferent fibers undergo structural changes in DPN; however, the exact functional contributions of these changes to DPN symptomology are unknown, necessitating animal studies. This review first presents the commonly used mouse models of DPN resulting from both type 1 and type 2 DM. It then discusses structural changes in Aβ, Aδ, and C fibers throughout the progression of DPN and their respective contributions to painful DPN in both human patients and DM mouse models. Finally, it highlights remaining questions on sensory neuron structure-function relationships in painful DPN and how we may address these in mouse models by using technological advances in cell-specific modulation. Only when these structure-function relationships are understood, can novel targeted therapeutics be developed for DPN.
Learn More >Tanezumab, a humanized monoclonal anti-NGF antibody, has demonstrated efficacy and safety profiles in Phase III clinical trials of chronic pain. In a 24-week study in non-human primates, morphological observations of sympathetic ganglia showed decreased ganglia volume, decreased neuronal size, and increased glial cell density compared with controls after 3 tanezumab treatments. Using stereological techniques to quantify glial cells, the present 26-week study found no significant difference after weekly treatments in total cervicothoracic ganglia satellite glial cell number between placebo- or tanezumab-treated cynomolgus monkeys. These findings suggest that tanezumab treatment does not result in a true gliosis in sympathetic ganglia.
Learn More >Presynaptic N-methyl-D-aspartate receptors contribute to opioid tolerance and hyperalgesia as well as neuropathic painThe α2δ-1 protein subunit enhances presynaptic N-methyl-D-aspartate receptor activity WHAT THIS ARTICLE TELLS US THAT IS NEW: Using mouse and rat models, it was demonstrated that α2δ-1 is essential for the increase in presynaptic N-methyl-D-aspartate receptor activity seen during chronic morphine exposureInhibiting α2δ-1 activity using gabapentin or genetically deleting the gene coding for α2δ-1 results in diminished opioid tolerance and hyperalgesia BACKGROUND:: Chronic use of μ-opioid receptor agonists paradoxically causes both hyperalgesia and the loss of analgesic efficacy. Opioid treatment increases presynaptic N-methyl-D-aspartate receptor activity to potentiate nociceptive input to spinal dorsal horn neurons. However, the mechanism responsible for this opioid-induced activation of presynaptic N-methyl-D-aspartate receptors remains unclear. α2δ-1, formerly known as a calcium channel subunit, interacts with N-methyl-D-aspartate receptors and is primarily expressed at presynaptic terminals. This study tested the hypothesis that α2δ-1-bound N-methyl-D-aspartate receptors contribute to presynaptic N-methyl-D-aspartate receptor hyperactivity associated with opioid-induced hyperalgesia and analgesic tolerance.
Learn More >Chronic neuropathic pain is a debilitating condition that remains challenging to treat. Glutamate N-methyl-D-aspartate receptor (NMDAR) antagonists have been used to treat neuropathic pain, but the exact sites of their actions have been unclear until recently. Although conventionally postsynaptic, NMDARs are also expressed presynaptically, particularly at the central terminals of primary sensory neurons, in the spinal dorsal horn. However, presynaptic NMDARs in the spinal cord are normally quiescent and are not actively involved in physiological nociceptive transmission. In this review, we describe the emerging role of presynaptic NMDARs at the spinal cord level in chronic neuropathic pain and the implications of molecular mechanisms for more effective treatment. Recent studies indicate that presynaptic NMDAR activity at the spinal cord level is increased in several neuropathic pain conditions but not in chronic inflammatory pain. Increased presynaptic NMDAR activity can potentiate glutamate release from primary afferent terminals to spinal dorsal horn neurons, which is crucial for the synaptic plasticity associated with neuropathic pain caused by traumatic nerve injury and chemotherapy-induced peripheral neuropathy. Furthermore, α2δ-1, previously considered a calcium channel subunit, can directly interact with NMDARs through its C-terminus to increase presynaptic NMDAR activity by facilitating synaptic trafficking of α2δ-1-NMDAR complexes in neuropathic pain caused by chemotherapeutic agents and peripheral nerve injury. Targeting α2δ-1-bound NMDARs with gabapentinoids or α2δ-1 C-terminus peptides can attenuate nociceptive drive form primary sensory nerves to dorsal horn neurons in neuropathic pain.
Learn More >This article presents the results of a parallel-group, non-randomized, controlled study that evaluated the feasibility of an online training program for improving observer detection of facial pain expression.
Learn More >To assess efficacy and safety of lidocaine 700 mg medicated plaster (lidocaine plaster) compared to placebo in patients with moderate to severe chronic post-surgical neuropathic pain (PSNP).
Learn More >Spinal cord stimulation (SCS), based on the gate theory of nociception, has been shown to be effective in the management of chronic pain conditions. While early-generation technology offered many patients improvement in their pain and symptoms, limitations including paresthesia, dependence on mapping, decreased chronological efficacy, and inadequate coverage left many patients with persistent pain and overt therapeutic failure.
Learn More >The traditional translational approach in neuropathic pain research has mainly consisted to date in translating basic findings from animal models of nerve injury to the clinic. Because of the difficulty to extrapolate mechanisms from animals to humans, an inverse translational approach ("top-down") has been advocated and contributed to the development of therapy. In particular, a number of treatments such as neurostimulation techniques have been initially assessed in patients and then translated to animal models for further investigation of their mechanisms. Therapeutic approaches based on an in-depth assessment of sensory phenotypes, suggestive of mechanisms, have also been implemented. The biggest trend in recent translational research is to investigate mechanisms or predict therapeutic response in patients by integrating multimodal approaches. The present narrative review emphasizes these various aspects of translational research in neuropathic pain.
Learn More >Neuropathic pain encompasses a diverse array of clinical entities affecting 7-10% of the population, which is challenging to adequately treat. Several promising therapeutics derived from molecular discoveries in animal models of neuropathic pain have failed to translate following unsuccessful clinical trials suggesting the possibility of important cellular-level and molecular differences between animals and humans. Establishing the extent of potential differences between laboratory animals and humans, through direct study of human tissues and/or cells, is likely important in facilitating translation of preclinical discoveries to meaningful treatments. Patch-clamp electrophysiology and RNA-sequencing was performed on dorsal root ganglia taken from patients with variable presence of radicular/neuropathic pain. Findings establish that spontaneous action potential generation in dorsal root ganglion neurons is associated with radicular/neuropathic pain and radiographic nerve root compression. Transcriptome analysis suggests presence of sex-specific differences and reveals gene modules and signalling pathways in immune response and neuronal plasticity related to radicular/neuropathic pain that may suggest therapeutic avenues and that has the potential to predict neuropathic pain in future cohorts.
Learn More >The advent of anti-CGRP medications is an example of translational research made real. Pioneering research by Drs. Lars Edvinsson and Peter Goadsby has yielded the monoclonal antibody therapeutics and will likely also result in the gepants. The availability of MABs represents a watershed moment in the treatment of migraine. These medications have specificity, as they were designed for primary migraine prevention. They work across a group of wide therapeutic targets, episodic migraine, chronic migraine, medication-overuse headache, and episodic cluster headache. They separate from placebo within 1 week, and often show clinical effects within a month or less. They have tolerability similar to placebo. There has been no significant or worrisome safety signal thus far in their use. They manifest unprecedented responder rates at ≥ 75% and even 100%. They lower all acute medication use and can convert patients from chronic migraine to episodic migraine and from acute medication overuse to non-overuse. They work in patients who have already had lack of success with at least 2-4 previous preventive medications. Pent-up demand for designer, well-tolerated, and effective migraine preventive medication in the USA has resulted in more than 100,000 individual patients prescribed erenumab from May to December of 2018, and the numbers continue to increase. The preventive treatment of migraine in the USA has shifted dramatically, and is likely to do so in the rest of the world as well.
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