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The peripheral nervous system has important regenerative capacities that regulate and restore peripheral nerve homeostasis. Following peripheral nerve injury, the nerve undergoes a highly regulated degeneration and regeneration process called Wallerian degeneration, where numerous cell populations interact to allow proper nerve healing. Recent studies have evidenced the prominent role of morphogenetic Hedgehog signaling pathway and its main effectors, Sonic Hedgehog (SHH) and Desert Hedgehog (DHH) in the regenerative drive following nerve injury. Furthermore, dysfunctional regeneration and/or dysfunctional Hedgehog signaling participate in the development of chronic neuropathic pain that sometimes accompanies nerve healing in the clinical context. Understanding the implications of this key signaling pathway could provide exciting new perspectives for future research on peripheral nerve healing.
Learn More >Spinal cord stimulation (SCS) is an approved treatment for truncal and limb neuropathic pain. However, pain relief is often suboptimal and SCS efficacy may reduce over time, sometimes requiring addition of other pain therapies, stimulator revision, or even explantation. We designed and tested a new procedure by combining SCS with immersive virtual reality (VR) to enable analgesia in patients with chronic leg pain. We coupled SCS and VR by linking SCS-induced paresthesia with personalized visual bodily feedback that was provided by VR and matched to the spatio-temporal patterns of SCS-induced paresthesia. In this cross-sectional prospective interventional study, fifteen patients with severe chronic pain and an SCS implant underwent congruent SCS-VR (personalized visual feedback of the perceived SCS-induced paresthesia displayed on the patient's virtual body) and two control conditions (incongruent SCS-VR; VR alone). We demonstrate the efficacy of neuromodulation-enhanced VR for the treatment of chronic pain by showing that congruent SCS-VR reduced pain ratings on average by 44%. SCS-VR analgesia was stronger than in both control conditions (enabling stronger analgesic effects than incongruent SCS-VR analgesia or VR alone), and kept increasing over successive stimulations, revealing the selectivity and consistency of the observed effects. We also show that analgesia persists after congruent SCS-VR had stopped, indicating carry over effects and underlining its therapeutic potential. Linking latest VR technology with recent insights from the neuroscience of body perception and SCS-neuromodulation, our personalized new SCS-VR platform highlights the impact of immersive digiceutical therapies for chronic pain.
Learn More >Long-term follow-up of patients treated with open-label placebo (OLP) are non-existent. Herein, we report a 5-year follow-up of a three-weeks OLP randomized controlled trial (RCT) in chronic low back pain patients. We re-contacted the original participants of original RCT and reassessed their pain, disability, and use of pain medication. We obtained follow-up data from 55 participants (82% of those who took OLP during the parent RCT), with a mean elapsed time between the end of the 3-weeks placebo trial and the follow-up interview of 55 months (SD=7.85). We found significant reductions in both pain and disability between the baseline assessment immediately before the three-weeks trial with placebo pills and the original trial endpoint (p < .00001 for the two primary outcomes of pain and disability). At the 5-year follow-up, we found no significant differences in either outcome between original trial endpoint and follow-up. Improvements persisted after 5-years and were accompanied by substantial reductions compared to baseline in the use of pain medication (from 87% to 38%), comprising analgesics (from 80% to 31%) antidepressants (from 24% to 11%), and benzodiazepines (from 15% to 5%). In contrast, the use of alternative approaches to pain management increased (from 18% to 29%). Although the reduction in pain and medication is comparable to the improvements that occurred in the original study, a major limitation of this long-term follow-up is the absence of controls for spontaneous improvement and new co-interventions. Nonetheless, our data suggest that reductions in pain and disability following OLP may be long lasting.
Learn More >Traditional classification and prognostic approaches for chronic pain conditions focus primarily on anatomically based clinical characteristics not based on underlying biopsychosocial factors contributing to perception of clinical pain and future pain trajectories. Using a supervised clustering approach in a cohort of temporomandibular disorder (TMD) cases and controls from the Orofacial Pain: Prospective Evaluation and Risk Assessment (OPPERA) study, we recently developed and validated a rapid algorithm (ROPA) to pragmatically classify chronic pain patients into three groups that differed in clinical pain report, biopsychosocial profiles, functional limitations, and comorbid conditions. The present aim was to examine the generalizability of this clustering procedure in two additional cohorts: a cohort of patients with chronic overlapping pain conditions (Complex Persistent Pain Conditions (CPPC) study), and a real-world clinical population of patients seeking treatment at Duke Innovative Pain Therapies (DIPT). In each cohort, we applied ROPA for cluster prediction, which requires only four input variables: pressure pain threshold (PPT) and anxiety, depression, and somatization scales. In both CPPC and DIPT, we distinguished three clusters, including one with more severe clinical characteristics and psychological distress. We observed strong concordance with observed cluster solutions, indicating the ROPA method allows for reliable subtyping of clinical populations with minimal patient burden. The ROPA clustering algorithm represents a rapid and valid stratification tool independent of anatomic diagnosis. ROPA holds promise in classifying patients based on pathophysiological mechanisms rather than structural or anatomical diagnoses. As such, this method of classifying patients will facilitate personalized pain medicine for patients with chronic pain.
Learn More >Neuropathic pain remains an undertreated condition and there is a medical need to develop effective treatments. Accumulating evidence indicates that post-transcriptional regulation of gene expression is involved in neuropathic pain; however, RNA processing is not clearly investigated. Our study investigated the role of HuR, an RNA binding protein, in promoting neuropathic pain and trauma-induced microglia activation in the spared nerve injury (SNI) mouse model. To this aim, an antisense oligonucleotide (ASO) knockdown of HuR gene expression was used. ASOs poorly cross the blood brain barrier and an intranasal (i.n.) administration was employed to achieve CNS penetration through a noninvasive delivery. The efficacy of i.n. ASO administration was compared to an intrathecal (i.t.) delivery. I.n. administered ASO reduced spinal HuR protein and relieved pain hypersensitivity with a similar efficacy to i.t. administration. Immunofluorescence studies showed that HuR was expressed in activated microglia, co-localized with p38 and, partially, with extracellular signal-regulated kinase (ERK)1/2 within the spinal cord dorsal horn. An anti-HuR ASO inhibited the activation of spinal microglia by reducing the levels of pro-inflammatory cytokines, inducible nitric oxide synthase (iNOS), the activation of nuclear factor-κB (NF-κB), and suppressed the SNI-induced overphosphorylation of spinal p38, ERK1/2 and c-Jun-N-terminal kinase (JNK)-1. In addition, HuR silencing increased the expression of the anti-inflammatory cytokine IL-10, promoting the shift of microglial M1 to M2 phenotype. Targeting HuR by i.n. anti-HuR ASO might represent a noninvasive promising perspective for neuropathic pain management by its powerful inhibition of microglia-mediated spinal neuroinflammation and promotion of an anti-inflammatory and neuroprotectant response.
Learn More >Severe neuropathic pain is a hallmark of Fabry disease, a genetic disorder caused by a deficiency in lysosomal α-Galactosidase A. Pain experienced by these patients significantly impacts their quality of life and ability to perform everyday tasks. Fabry patients suffer from peripheral neuropathy, sensory abnormalities, acute pain crises, and lifelong ongoing pain. Although treatment of pain through medication and enzyme replacement therapy (ERT) exists, pain persists in many of these patients. Some has been learned in the past decades regarding clinical manifestations of pain in Fabry disease and the pathological effects of α-Galactosidase A insufficiency in neurons. Still, it is unclear how pain and sensory abnormalities arise in Fabry patients and how these can be targeted with therapeutics. Our knowledge is limited in part due to the lack of adequate preclinical models to study the disease. This review will detail the types of pain, sensory abnormalities, influence of demographics on pain, and current strategies to treat pain experienced by Fabry patients. In addition, we discuss the current knowledge of Fabry pain pathogenesis and which aspects of the disease preclinical models accurately recapitulate. Understanding the commonalities and divergences between humans and preclinical models can be utilized to further interrogate mechanisms causing the pain and sensory abnormalities as well as advance development of the next generation of therapeutics to treat pain in Fabry patients.
Learn More >It has been proposed that Complex Regional Pain Syndrome (CRPS) is a post-traumatic autoimmune disease. Previously we observed that B cells contribute to CRPS-like changes in a mouse tibia fracture model, and that early (< 12 months duration) CRPS patient IgM antibodies have pronociceptive effects in the skin and spinal cord of muMT fracture mice lacking B cells. The current study evaluated the pronociceptive effects of intraplantar or intrathecal injections of early CRPS IgM (5ug) in muMT fracture mice. Skin and lumbar spinal cord were collected for immunohistochemistry and polymerase chain reaction (PCR) analyses. Wildtype mice exhibited post fracture increases in complement component C5a and its receptor expression in skin and spinal cord, predominantly on dermal macrophages and spinal microglia. Intraplantar IgM injection caused nociceptive sensitization in muMT fracture mice with increased complement component C1q and inflammatory cytokine expression, and these IgM effects were blocked by a C5a receptor antagonist (PMX53) or a global cytokine inhibitor (pentoxifylline). Intrathecal IgM injection also had pronociceptive effects with increased spinal cytokine expression, effects that were blocked by PMX53 or pentoxifylline treatment. Intrathecal injection of chronic (> 12 months duration) CRPS patient IgM (but not IgG) caused nociceptive sensitization in muMT fracture mice, but intraplantar injection of chronic CRPS IgM or IgG had no effect. We postulate that CRPS IgM antibodies bind to neoantigens in the fracture limb skin and corresponding spinal cord to activate C5a complement signaling in macrophages and microglia, evoking proinflammatory cytokine expression contributing to nociceptive sensitization in the injured limb.
Learn More >Early life abuse (ELAb) initiates pathophysiological cascades resulting in long-term maladaptive stress responsivity, hyperalgesia and an increased risk for psychopathology. Mindfulness-based stress reduction (MBSR) is effective in modifying psychological and somatic symptoms; thus, we predicted that MBSR would be particularly efficacious for women with ELAb.
Learn More >More than 750,000 people in the United States died from an overdose between 1999 and 2018; two-thirds of those deaths involved an opioid. In this review, we present trends in opioid overdose rates during this period and discuss how the proliferation of opioid prescribing to treat chronic pain, changes in the heroin and illegally manufactured opioid synthetics markets, and social factors, including deindustrialization and concentrated poverty, contributed to the rise of the overdose epidemic. We also examine how current policies implemented to address the overdose epidemic may have contributed to reducing prescription opioid overdoses but increased overdoses involving illegal opioids. Finally, we identify new directions for research to understand the causes and solutions to this critical public health problem, including research on heterogeneous policy effects across social groups, effective approaches to reduce overdoses of illegal opioids, and the role of social contexts in shaping policy implementation and impact. Expected final online publication date for the , Volume 42 is April 1, 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
Learn More >Inflammatory pain activates astrocytes and increases inflammatory cytokine release in the spinal cord. Mitochondrial fusion and fission rely on the functions of dynamin-related protein 1 (Drp1) and optic atrophy 1 (OPA1), which are essential for the synaptic transmission and plasticity. In the present study, we aimed to explore the effects of 2-bromopalmitate (2-BP), an inhibitor of protein palmitoylation, on the modulation of pain behavior. Rats were intraplantar injected with complete Freund's adjuvant (CFA) to establish an inflammatory pain model. In the spinal cord of rats with CFA-induced inflammatory pain, the expression of astrocyte-specific glial fibrillary acidic protein (GFAP) and contents of proinflammatory cytokines IL-1β and TNF-α were increased. Mitochondrial Drp1 was increased, while OPA1 was decreased. Consequently, CFA induced reactive oxygen species (ROS) production and Bcl-2-associated X protein (BAX) expression. The intrathecal administration of 2-BP significantly reversed the pain behaviors of the inflammatory pain in rats. Moreover, 2-BP also reduced the Drp1 expression, elevated the OPA1 expression, and further reduced the GFAP, IL-1β, and TNF-α expression and ROS production. Furthermore, in vitro study proved a similar effect of 2-BP on the regulation of Drp1 and OPA1 expression. 2-BP also increased the mitochondrial membrane potential and decreased the levels of BAX, ROS, and proinflammatory cytokines. These results indicate that 2-BP may attenuate the inflammatory pain of CFA-treated rats via regulating mitochondrial fission/fusion balance and function.
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