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Children of mothers with chronic pain are at increased risk for poor health, but few studies have examined what characteristics of maternal chronic pain may be associated with children's risk. This study identified subgroups of mothers based on patterns of pain, physical function, and emotional function on the 29-item Patient-Reported Outcomes Measurement Information System® (PROMIS-29®) and evaluated associations between maternal subgroups and children's pain and emotional functioning.
Learn More >This review expounds on types and properties of biomarkers for chronic pain, given a mechanistic model of processes underlying development of chronic pain. It covers advances in the field of developing biomarkers for chronic pain, while outlining the general principles of categorizing types of biomarkers driven by specific hypotheses regarding underlying mechanisms. Within this theoretical construct, example biomarkers are described and their properties expounded. We conclude that the field is advancing in important directions and the developed biomarkers have the potential of impacting both the science and the clinical practice regarding chronic pain.
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 >The peripherally expressed voltage-gated sodium Na1.7 (gene SCN9A) channel boosts small stimuli to initiate firing of pain-signaling dorsal root ganglia (DRG) neurons and facilitates neurotransmitter release at the first synapse within the spinal cord. Mutations in SCN9A produce distinct human pain syndromes. Widely acknowledged as a "gatekeeper" of pain, Na1.7 has been the focus of intense investigation but, to date, no Na1.7-selective drugs have reached the clinic. Elegant crystallographic studies have demonstrated the potential of designing highly potent and selective Na1.7 compounds but their therapeutic value remains untested. Transcriptional silencing of Na1.7 by a naturally expressed antisense transcript has been reported in rodents and humans but whether this represents a viable opportunity for designing Na1.7 therapeutics is currently unknown. The demonstration that loss of Na1.7 function is associated with upregulation of endogenous opioids and potentiation of mu- and delta-opioid receptor activities, suggests that targeting only Na1.7 may be insufficient for analgesia. However, the link between opioid-dependent analgesic mechanisms and function of sodium channels and intracellular sodium-dependent signaling remains controversial and disputed. Thus, additional new targets – regulators, modulators – are needed. In this context, we mine the literature for the known interactome of Na1.7 with a focus on protein interactors that affect the channel's trafficking or link it to opioid signaling. As a case study, we present antinociceptive evidence of allosteric regulation of Na1.7 by the cytosolic collapsin response mediator protein 2 (CRMP2). Throughout discussions of these possible new targets, we offer thoughts on the therapeutic implications of modulating Na1.7 function in chronic pain.
Learn More >To study the impact of therapeutic interventions on pain analgesia and endogenous pain modulation in knee osteoarthritis (KOA).
Learn More >Opioid misuse and abuse in the USA has evolved into an epidemic of tragic pain and suffering, resulting in the estimated death of over 64,000 people in 2016. Governmental regulation has escalated alongside growing awareness of the epidemic's severity, both on the state and federal levels.
Learn More >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 >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.
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