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Medication Overuse Headache (MOH) is a prevalent and disabling disorder resulting from the overuse of analgesic drugs, triptans or other acute headache medications. In previous proteomic studies, several proteins have been found at high concentrations in the urine of MOH patients and in the serum of rats with neuropathic pain. The aim of this study was to compare the serum levels of lipocalin-type Prostaglandin D2 synthase (L-PGDS), Vitamin D-binding protein (VDBP), apolipoprotein E (APOE) and apolipoprotein A1 (APOA1) in MOH patients and healthy individuals, further exploring their relationship with cutaneous pain thresholds (CPTs) in the territories innervated by the trigeminal nerve.
Learn More >Although dysfunction of the mesolimbic dopaminergic system has been implicated in chronic pain, the underlying mechanisms remain to be elucidated. We hypothesized that increased inhibitory inputs to the neuronal pathway from the dorsolateral bed nucleus of the stria terminalis (dlBNST) to the ventral tegmental area (VTA) during chronic pain may induce tonic suppression of the mesolimbic dopaminergic system. To test this hypothesis, male Sprague-Dawley rats were subjected to spinal nerve ligation to induce neuropathic pain and then spontaneous inhibitory postsynaptic currents (sIPSCs) were measured in this neuronal pathway. Whole-cell patch-clamp electrophysiology of brain slices containing the dlBNST revealed that the frequency of sIPSCs significantly increased in VTA-projecting dlBNST neurons 4 weeks after surgery. Next, the role of corticotropin-releasing factor (CRF) signaling within the dlBNST in the increased sIPSCs was examined. CRF increased the frequency of sIPSCs in VTA-projecting dlBNST neurons in sham-operated controls, but not in chronic pain rats. By contrast, NBI27914, a CRF type 1 receptor antagonist, decreased the frequency of sIPSCs in VTA-projecting dlBNST neurons in the chronic pain rats but not in the control animals. In addition, histological analyses revealed the increased expression of CRF mRNA in the dlBNST. Finally, bilateral injections of NBI27914 into the dlBNST of chronic pain rats activated mesolimbic dopaminergic neurons and induced conditioned place preference. Taken together, these results suggest that the mesolimbic dopaminergic system is tonically suppressed during chronic pain by enhanced CRF signaling within the dlBNST via increased inhibitory inputs to VTA-projecting dlBNST neurons.The comorbidity of chronic pain and depression has long been recognized. Although dysfunction of the mesolimbic dopaminergic system has been implicated in both chronic pain and depression, the underlying mechanisms remain to be elucidated. Here we show that the inhibitory inputs to the neuronal pathway from the dorsolateral bed nucleus of the stria terminalis (dlBNST) to the ventral tegmental area increase during chronic pain. This neuroplastic change is mediated by enhanced corticotropin-releasing factor signaling within the dlBNST that leads to tonic suppression of the mesolimbic dopaminergic system, which may be involved in the depressive mood and anhedonia under the chronic pain condition.
Learn More >α-Conotoxin Vc1.1 inhibits the nicotinic acetylcholine receptor (nAChR) α9α10 subtype and has the potential to treat neuropathic chronic pain. To date, the crystal structure of Vc1.1 bound-α9α10 nAChR remains unavailable, thus understanding the structure-activity relationship of Vc1.1 with the α9α10 nAChR remains challenging. In this study, the Vc1.1 side chains were minimally modified to avoid introducing large local conformation perturbation to the interactions between Vc1.1 and α9α10 nAChR. The results suggest that the hydroxyl group of Vc1.1 Y10 forms hydrogen bond with the carbonyl group of α9 N107 and a hydrogen bond donor is required, whereas Vc1.1 S4 is adjacent to the α9 D166 and D169, and a positive charge residue at this position increases the binding affinity of Vc1.1. Furthermore, the carboxyl group of Vc1.1 D11 forms two hydrogen bonds with α9 N154 and R81 respectively, whereas introducing an extra carboxyl group at this position significantly decreases the potency of Vc1.1. Second generation mutants of Vc1.1 [S4Dab, N9A] and [S4Dab, N9W] increased potency at the α9α10 nAChR by 20-fold compared with that of Vc1.1. The [S4Dab, N9W] mutational effects at positions 4 and 9 of Vc1.1 are not cumulative but are coupled with each other. Overall, our findings provide valuable insights into the structure-activity relationship of Vc1.1 with the α9α10 nAChR and will contribute to further development of more potent and specific Vc1.1 analogues.
Learn More >Regulator of G protein signaling 4 (RGS4) is a potent modulator of G protein-coupled receptor (GPCR) signal transduction that is expressed throughout the pain matrix. Here, we use genetic mouse models to demonstrate a role of RGS4 in the maintenance of chronic pain states in male and in female mice. Using paradigms of peripheral inflammation and nerve injury, we show that prevention of RGS4 action leads to recovery from mechanical and cold hypersensitivity and increases motivation for wheel running. Similarly, RGS4KO eliminates the duration of nocifensive behavior in the second phase of the formalin assay. Using the Complete Freud's adjuvant (CFA) model of hind paw inflammation we also demonstrate that downregulation of RGS4 in the adult ventral posterolateral thalamic nuclei (VPL-THL) promotes recovery from mechanical and cold allodynia. RNA sequencing analysis of thalamus (THL) from RGS4WT and RGS4KO mice points to many signal transduction modulators and transcription factors that are uniquely regulated in CFA-treated RGS4WT cohorts. Ingenuity Pathway Analysis suggests that several components of glutamatergic signaling are differentially affected by CFA treatment between RGS4WT and RGS4KO groups. Notably, western blot analysis shows increased expression of metabotropic glutamate receptor 2 (mGluR2) in THL synaptosomes of RGS4KO mice at time points at which they recover from mechanical allodynia. Overall, our study provides information on a novel intracellular pathway that contributes to the maintenance of chronic pain states and points to RGS4 as a potential therapeutic target.There is an imminent need for safe and efficient chronic pain medications. RGS4 is a multifunctional signal transduction protein, widely expressed in the pain matrix. Here, we demonstrate that RGS4 plays a prominent role in the maintenance of chronic pain symptoms in male and female mice. Using genetically modified mice we show a dynamic role of RGS4 in recovery from symptoms of sensory hypersensitivity deriving from hind paw inflammation or hind limb nerve injury. We also demonstrate an important role of RGS4 actions in gene expression patterns induced by chronic pain states in the mouse thalamus. Our findings provide novel insight into mechanisms associated with the maintenance of chronic pain states and demonstrate that interventions in RGS4 activity promote recovery from sensory hypersensitivity symptoms.
Learn More >Knowledge of efficacious dosing respective to exercise type and pain condition is extremely limited in the literature. This study aimed to determine the impact of dose of moderate intensity treadmill walking on experimentally-induced pain in healthy human participants. Forty females were divided into 4 groups: control (no exercise), low dose exercise (3×/wk), moderate dose exercise (5×/wk) or high dose exercise (10×/wk). Over a 7-day period, subjects performed treadmill walking during assigned exercise days. Both qualitative and quantitative measures of pain were measured at baseline, during the trial, and 24 hrs post-final intervention session via sensitivity thresholds to painful thermal and painful pressure stimulation. Significant effects of treatment were found post-intervention for constant pressure pain intensity (p = 0.0016) and pain unpleasantness ratings (p = 0.0014). Post-hoc tests revealed significant differences between control and moderate and control and high dose groups for constant pressure pain intensity (p = 0.0015), (p = 0.0094), respectively and constant pressure pain unpleasantness (p = 0.0040), (p = 0.0040), respectively. Moderate and high dose groups had the greatest reductions in ratings of pain, suggesting that our lowest dose of exercise was not sufficient to reduce pain and that the moderate dose of exercise may be a sufficient starting dose for exercise-based adjuvant pain therapy.
Learn More >Opioids are the mainstay of pain management after burn injury. The United States currently faces an epidemic of opioid overuse and abuse, while simultaneously experiencing a nationwide shortage of intravenous narcotics. Adjunctive pain management therapies must be sought and utilized to reduce the use of opioids in burn care to prevent the long-term negative effects of these medications and to minimize the dependence on opioids for analgesia. The purpose of this review was to identify literature on adjunctive pain management therapies that have been demonstrated to reduce pain severity or opioid consumption in adult burn patients. Three databases were searched for prospective studies, randomized controlled trials, and systematic reviews that evaluated adjunctive pain management strategies published between 2008 and 2019 in adult burn patients. Forty-six studies were analyzed, including 24 randomized control trials, six crossover trials, and ten systematic reviews. Various adjunctive pain management therapies showed statistically significant reduction in pain severity. Only one randomized control trial on music therapy for acute background pain showed a reduction in opioid use. One cohort study on hypnosis demonstrated reduced opioid use compared with historical controls. We recommend the development of individualized analgesic regimens with the incorporation of adjunctive therapies in order to improve burn pain management in the midst of an abuse crisis and concomitant national opioid shortage.
Learn More >Long-term trials are key to understanding chronic symptoms such as pain and itch. However, challenges such as high attrition rates and poor recruitment are common when conducting research. The aim of this work is to explore these issues within a long-term randomized control trial using transcranial direct current stimulation to treat pain and itch. This parallel double blinded, placebo-controlled randomized trial was comprised of 15 transcranial direct current stimulation visits and 7 follow-up visits. Participants were over the age of 18, had a burn injury that occurred at least 3 weeks prior to enrollment, and reported having pain and/or itch that was moderate to severe in intensity. A total of 31 subjects were randomized into either an active or sham transcranial direct current stimulation groups. There were no significant differences between the groups in terms of age, race, education, baseline depression, or anxiety. The median dropout time was at visit 19 [visit 16 (SE=1.98) for the sham group and visit 19 (SE=1.98) for the active group]. Analysis showed no differences in the dropout rate between groups (χ2(1)=0.003, p=0.954). The dropout rate was 46.7% for the sham group and 43.8% for the active group. Overall, 45.2% of the subjects dropped out of the trial. Long-term clinical trials are an essential part of evaluating interventions for symptoms such as chronic pain and itch. However, as seen in this trial, long-term studies in the burn population often face recruitment and adherence challenges.
Learn More >HIV-1 infection of the nervous system causes various neurological diseases, and synaptic degeneration is likely a critical step in the neuropathogenesis. Our prior studies revealed a significant decrease of synaptic protein specifically in the spinal dorsal horn (SDH) of HIV-1 patients who developed pain, suggesting a potential contribution of synaptic degeneration to the pathogenesis of HIV-associated pain. However, the mechanism by which HIV-1 causes the spinal synaptic degeneration is unclear. Here, we identified a critical role of microglia in the synaptic degeneration. In primary cortical cultures (DIV14) and spinal cords of 3-5-month-old mice (both genders), microglial ablation inhibited gp120-induced synapse decrease. Fractalkine (FKN), a microglia-activation chemokine specifically expressed in neurons, was up-regulated by gp120, and knockout of the FKN receptor CX3CR1, which is predominantly expressed in microglia, protected synapses from gp120-induced toxicity. These results indicate the neuron-to-microglia intercellular FKN/CX3CR1 signaling plays a role in gp120-induced synaptic degeneration. To elucidate the mechanism controlling this intercellular signaling, we tested the role of the Wnt/β-catenin pathway in regulating FKN expression. Inhibition of Wnt/β-catenin signaling blocked both gp120-induced FKN up-regulation and synaptic degeneration, and gp120 stimulated Wnt/β-catenin-regulated FKN expression via NMDA receptors. Furthermore, NMDAR antagonist APV, Wnt/β-catenin signaling suppressor DKK1 or knockout of CX3CR1 alleviated gp120-induced mechanical allodynia in mice, suggesting a critical contribution of the Wnt/β-catenin/FKN/CX3R1 pathway to gp120-induced pain. These findings collectively suggest that HIV-1 gp120 induces synapse degeneration in the spinal pain neural circuit by activating microglia via Wnt3a/β-catenin-regulated FKN expression in neurons.HIV patients with chronic pain develop synaptic degeneration in the spinal cord dorsal horn, but the patients without the pain disorder do not show this neuropathology, indicating a pathogenic contribution of the synaptic degeneration to the development of HIV-associated pain. However, the mechanism underlying the synaptic degeneration is unclear. We report here that HIV-1 gp120, a neurotoxic protein that is specifically associated with the manifestation of pain in HIV patients, induces synapse loss via microglia. Further studies elucidate that gp120 activates microglia by stimulating Wnt/β-catenin-regulated fractalkine in neuron. The results demonstrate a critical role of microglia in the pathogenesis of HIV-associated synaptic degeneration in the spinal pain neural circuit.
Learn More >Antineoplastic drugs induce dramatic transcriptional changes in dorsal root ganglion (DRG) neurons, which may contribute to chemotherapy-induced neuropathic pain. K 1.1 controls neuronal excitability by setting the resting membrane potential. Here, we report that systemic injection of the chemotherapy agent paclitaxel time-dependently downregulates the expression of K 1.1 mRNA and its coding K 1.1 protein in the DRG neurons. Rescuing this downregulation mitigates the development and maintenance of paclitaxel-induced mechanical allodynia and heat hyperalgesia. Conversely, in the absence of paclitaxel administration, mimicking this downregulation decreases outward potassium current and increases excitability in the DRG neurons, leading to the enhanced responses to mechanical and heat stimuli. Mechanically, the downregulation of DRG K 1.1 mRNA is attributed to paclitaxel-induced increase in DRG DNMT3a, as blocking this increase reverses the paclitaxel-induced the decrease of DRG K 1.1 and mimicking this increase reduces DRG K 1.1 expression. In addition, paclitaxel injection increases the binding of DNMT3a to the K 1.1 gene promoter region and elevates the level of DNA methylation within this region in the DRG. These findings suggest that DNMT3a-triggered downregulation of DRG K 1.1 may contribute to chemotherapy-induced neuropathic pain. This article is protected by copyright. All rights reserved.
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