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Peripheral nerve injury elicits an enduring increase in the excitability of the spinal dorsal horn. This change, which contributes to the development of neuropathic pain, is a consequence of release and prolonged exposure of dorsal horn neurons to various neurotrophins and cytokines. We have shown in rats that nerve injury increases excitatory synaptic drive to excitatory neurons but decreases drive to inhibitory neurons. Both effects, which contribute to an increase in dorsal horn excitability, appear to be mediated by microglial-derived BDNF. We have used multiphoton Ca imaging and whole-cell recording of spontaneous EPSC's in defined medium organotypic cultures of GAD67-GFP+ mice spinal cord to determine the receptor dependence of these opposing actions of BDNF. In mice, as in rats, BDNF enhances excitatory transmission onto excitatory neurons. This is mediated via presynaptic TrkB and p75 neurotrophin receptors and exclusively by postsynaptic TrkB. By contrast with findings from rats, in mice BDNF does not decrease excitation of inhibitory neurons. The cytokine, macrophage colony stimulating factor 1 (CSF-1) has also been implicated in the onset of neuropathic pain. Nerve injury provokes its synthesis in primary afferents, its release in spinal cord and activation of microglia. We now show that CSF-1 increases excitatory drive to excitatory neurons via a BDNF-dependent mechanism and decreases excitatory drive to inhibitory neurons via BDNF-independent processes. Our findings complete missing steps in the cascade of events whereby peripheral nerve injury instigates increased dorsal horn excitability in the context of central sensitization and the onset of neuropathic pain.
Learn More >Chronic neuropathic pain is a common challenging condition following amputation. Recent research demonstrated the feasibility of percutaneously implanting fine-wire coiled peripheral nerve stimulation (PNS) leads in proximity to the sciatic and femoral nerves for postamputation pain. A multicenter, double-blinded, randomized, placebo-controlled study collected data on the safety and effectiveness of percutaneous PNS for chronic neuropathic pain following amputation.
Learn More >Our understanding of how peripheral damage-sensing neurons (nociceptors) respond to noxious stimuli is fundamental to the development of effective analgesics. To date, numerous studies have presented diverging hypotheses on how nociceptors encode modality-specific stimuli, including labelled-line, intensity dependence or pattern theory. In this short review, we appraise data from electrophysiological, behavioural, imaging and molecular expression studies from the last 60 years, in order to obtain a coherent view of modality-specific sensing in peripheral sensory neurons. We propose a mechanistic explanation for the broad range of values obtained for the incidence of polymodal nociceptors that reconciles apparently contradictory data.
Learn More >Migraine is a common, highly disabling disorder. Its treatment involves acute and preventive therapy. Many of available preventive medications are not well tolerated, which results in poor compliance and limited effectiveness. Cannabinoids have been proposed for the treatment of migraine but their efficacy and tolerability are controversial.
Learn More >To conduct a systematic review on pain self-efficacy measures in children and adolescents. The review aims: (a) to summarize all self-report measures of pain self-efficacy that have been used with children and adolescents; (b) to rate the quality of these measures; (c) to summarize associations between pain self-efficacy and other constructs.
Learn More >The present study aimed to investigate cerebral metabolic changes in a neuropathic pain model following deafferentation. A total of 24 Sprague-Dawley rats were included for modeling of right brachial plexus avulsion (BPA) through the posterior approach. As nerve injury would cause central sensitization and facilitate pain sensitivity in other parts of the body, thermal withdrawal latency (TWL) of the intact forepaw was assessed to investigate the level of pain perception following BPA-induced neuropathic pain. [Fluorine-18]-fluoro-2-deoxy-D-glucose (F-FDG) positron emission tomography (PET) was applied to the brain before and after brachial plexus avulsion to explore metabolic changes in neuropathic pain following deafferentation. The TWL of the left (intact) forepaw was significantly lower after BPA than that of baseline (p<0.001). Using TWL as a covariate, standardized uptake values (SUVs) of F-FDG significantly increased in the ipsilateral dorsolateral thalamus and contralateral anterodorsal hippocampus after BPA. Conversely, SUVs in multiple brain regions decreased, including the contralateral somatosensory cortex, ipsilateral cingulate cortex, and ipsilateral temporal association cortex. The Pearson correlation analysis showed that the SUVs of the contralateral anterodorsal hippocampus and ipsilateral dorsolateral thalamus were negatively related to the TWL of the intact forepaw, whereas the SUVs in the contralateral somatosensory cortex and ipsilateral cingulate cortex were positively related to it (p<0.05). These findings indicate that upregulation of metabolism in the anterodorsal hippocampus and dorsolateral thalamus and downregulation metabolism in the contralateral somatosensory cortex and ipsilateral cingulate cortex could be a unique pattern of metabolic changes for neuropathic pain following brachial plexus avulsion.
Learn More >Neuropathic pain, resulting from somatosensory nervous system dysfunction, remains a serious public health problem worldwide. microRNAs are involved in the physiological processes of neuropathic pain. However, the biological roles of miR-98 in neuropathic pain development have not been investigated. Therefore, in our current study, we focused on the effects of miR-98 in neuropathic pain. It was shown that miR-98 was significantly downregulated in chronic sciatic nerve injury (CCI) rat models. In addition, high mobility group A2 (HMGA2) was obviously upregulated in CCI rats. Overexpression of miR-98 inhibited neuropathic pain progression, including mechanical and thermal hyperalgesia. By a bioinformatics analysis, HMGA2 was predicted as a direct target of miR-98. The negative correlation between miR-98 and HMGA2 was validated in our present study. Furthermore, overexpression of miR-98 dramatically repressed HMGA2 protein and messenger RNA (mRNA) expression. Neuroinflammation participates in neural-immune interactions, which can contribute to the neuropathic pain development. Meanwhile, we found that inflammatory cytokine (interleukin [IL]-6, IL-1β, and COX-2) protein expression in rats infected with LV-miR-98 was greatly suppressed. Taking these results together, we concluded that miR-98 might depress neuropathic pain development through modulating HMGA2.
Learn More >Low back pain (LBP) is an important medical and socioeconomic problem. Impaired sensorimotor control has been suggested to be a likely mechanism underlying development and/or maintenance of pain. Although early work focused on the structural and functional abnormalities within the musculoskeletal system, in the past 20 years there has been an increasing realization that patients with LBP might also have extensive neuroplastic changes within the central nervous system. These include changes related to both the structure (eg, gray matter changes) and function (eg, organization of the sensory and motor cortices) of the nervous system as related to processing of pain and nociception and to motor and somatosensory systems. Moreover, clinical interventions increasingly aim to drive neuroplasticity with treatments to improve pain and sensorimotor function. This commentary provides a contemporary overview of neuroplasticity of the pain/nociceptive and sensorimotor systems in LBP. This paper addresses (1) defining neuroplasticity in relation to control of the spine and LBP, (2) structural and functional nervous system changes as they relate to nonspecific LBP and sensorimotor function, and (3) related clinical implications. Individuals with recurrent and persistent LBP differ from those without LBP in several markers of the nervous system's function and structure. Neuroplastic changes may be addressed by top-down cognitive-based interventions and bottom-up physical interventions. An integrated clinical approach that combines contemporary pain neuroscience education, cognition-targeted sensorimotor control, and physical or function-based treatments may lead to better outcomes in patients with recurrent and persistent LBP. This approach will need to consider variation among individuals, as no single finding/mechanism is present in all individuals, and no single treatment that targets neuroplastic changes in the sensorimotor system is likely to be effective for all patients with LBP. .
Learn More >Chronic postsurgical pain is pain that develops and persists for at least 3 months after a surgical procedure. The purpose of this review was to discover what evidence exists regarding the influence of race and ethnicity on postoperative pain intensity and what evidence exists regarding the influence of genetic polymorphisms on postoperative pain intensity.
Learn More >Painful peripheral neuropathy is the most dose-limiting side effect of paclitaxel (PTX), a widely used anti-cancer drug to treat solid tumours. The understanding of the mechanisms involved in this side effect is crucial to the development of new therapeutic approaches. CXCL1 chemokine and its receptor CXCR2 have been pointed as promising targets to treat chronic pain. Herein, we sought to evaluate the possible involvement of CXCL1 and CXCR2 in the pathogenesis of PTX-induced neuropathic pain in mice. PTX treatment led to increased levels of CXCL1 in both dorsal root ganglion and spinal cord samples. Systemic treatment with the anti-CXCL1 antibody (10 μg/kg, i.v.) or the selective CXCR2 antagonist (SB225002, 3 mg/kg, i.p.) had minor effect on PTX-induced mechanical hypersensitivity. On the other hand, the intrathecal (i.t.) treatment with anti-CXCL1 (1 ng/site) or SB225002 (10 μg/site) consistently inhibited the nociceptive responses of PTX-treated mice. Similar results were obtained by inhibiting the PI3Kγ enzyme a downstream pathway of CXCL1/CXCR2 signalling with either the selective AS605240 (5 μg/site, i.t.) or the non-selective wortmannin PI3K inhibitor (0.4 μg/site, i.t.). Overall, the data indicates that the up-regulation of CXCL1 is important for the development and maintenance of PTX-induced neuropathic pain in mice. Therefore, the spinal blockage of CXCL1/CXCR2 signalling might be a new innovative therapeutic approach to treat this clinical side effect of PTX.
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