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Traumatic spinal cord injury (SCI) is a major cause of death and lifelong disability in the world. However, the pathological process of SCI has not been fully understood. F-box/WD repeat-containing protein 5 (FBXW5), a subunit of the SCF-type E3 ubiquitin ligase complex, plays an essential role in regulating various pathologies. However, little is known about the effects of FBXW5 on the progression of SCI. In this study, using a rodent model with SCI, we found that FBXW5 expression was markedly down-regulated in spinal dorsal horn of rats after SCI surgery. Rats with FBXW5 knockdown showed the improved paw withdrawal latency responding to thermal stimuli on the ipsilateral side while showed no significant influence on the basal threshold on the contralateral side. In addition, SCI-induced increase of pro-inflammatory cytokines, including tumor necrosis factor α (TNF-α), interleukin (IL)-1β and IL-6, was obviously decreased by FBXW5 knockdown, along with microglia inactivation as evidenced by the reduced expression of Iba-1. Moreover, immunofluorescent staining suggested that FBXW5 was co-localized with Iba-1 in spinal cord tissues of SCI rats. Furthermore, p38, Jun kinase (JNK) and extracellular signal-regulated kinase (ERK)-1/2 activation was significantly increased by SCI in spinal dosal horn of rats. Notably, FBXW5 knockdown markedly reduced the expression of phosphorylated p38 and JNK without affecting ERK1/2 activity in SCI rats. What's more, suppressing p38 and JNK activation significantly alleviated SCI-induced abnormal behavior in rats, along with reduced expression of pro-inflammatory cytokines. Taken together, these results provided evidence that down-regulation of FBXW5 was involved in the prevention of SCI.
Learn More >Spinal long-term potentiation (LTP) at C-fiber synapses is hypothesized to underlie chronic pain. However, a causal link between spinal LTP and chronic pain is still lacking. Here, we report that high-frequency stimulation (HFS; 100 Hz, 10 V) of the mouse sciatic nerve reliably induces spinal LTP without causing nerve injury. LTP-inducible stimulation triggers chronic pain lasting for more than 35 days and increases the number of calcitonin gene-related peptide (CGRP) terminals in the spinal dorsal horn. The behavioral and morphological changes can be prevented by blocking NMDA receptors, ablating spinal microglia, or conditionally deleting microglial brain-derived neurotrophic factor (BDNF). HFS-induced spinal LTP, microglial activation, and upregulation of BDNF are inhibited by antibodies against colony-stimulating factor 1 (CSF-1). Together, our results show that microglial CSF1 and BDNF signaling are indispensable for spinal LTP and chronic pain. The microglia-dependent transition of synaptic potentiation to structural alterations in pain pathways may underlie pain chronicity.
Learn More >Few studies have investigated the real-life outcomes of interdisciplinary multimodal pain rehabilitation programs (IMMRP) for chronic pain. This study has four aims: investigate effect sizes (ES); analyse correlation patterns of outcome changes; define a multivariate outcome measure; and investigate whether the clinical self-reported presentation pre-IMMRP predicts the multivariate outcome. To this end, this study analysed chronic pain patients in specialist care included in the Swedish Quality Registry for Pain Rehabilitation for 22 outcomes (pain, psychological distress, participation, and health) on three occasions: pre-IMMRP, post-IMMRP, and 12-month follow-up. Moderate stable ES were demonstrated for pain intensity, interference in daily life, vitality, and health; most other outcomes showed small ES. Using a Multivariate Improvement Score (MIS), we identified three clusters. Cluster 1 had marked positive MIS and was associated with the overall worst situation pre-IMMRP. However, the pre-IMMRP situation could only predict 8% of the variation in MIS. Specialist care IMPRPs showed moderate ES for pain, interference, vitality, and health. Outcomes were best for patients with the worst clinical presentation pre-IMMRP. It was not possible to predict who would clinically benefit most from IMMRP.
Learn More >Gabapentin has analgesic efficacy for neuropathic pain and is increasingly used in burn care. This study investigated the effect of a neuropathic pain control protocol, as well as early gabapentin initiation (< 72 hours from injury) on total inpatient opioid use, chronic pain, and itch. This is a single-institution retrospective cohort study of patients over age 14 admitted between 2006 and 2016 with burns. We compared patients who did not receive gabapentin with those who had early gabapentin initiation vs. late initiation. We also compared patients who used gabapentin prior to initiation of a neuropathic pain protocol (February 2015) to those after. Primary outcomes were total inpatient gabapentin, morphine equivalents (MED), longitudinal pain and itch, as well as SF-12v2 Health Survey mental and physical component scores (MCS/PCS) at discharge, 6, 12, and 24 months post-injury. Ordinal logistic regression analysis was used to examine pain and itch scores. Linear regression models examined MCS and PCS between groups. Models were adjusted for age, sex, TBSA burned, area grafted, MED, and ICU stay. There was no significant difference in MED with early initiation, yet inpatient gabapentin use increased from 43.9 g to 59.5 g (p<0.001) with late initiation. The neuropathic pain protocol did not significantly change total gabapentin use (p = 0.184) in patients receiving gabapentin but decreased opioid use from 58.1 g to 17.4 g MED (p = 0.008). Our results suggest neither early gabapentin nor its use in a standardization neuropathic pain protocol improves long-term pain, itch, PCS or MCS scores.
Learn More >Women manifest a higher prevalence of several chronic pain disorders compared to men. We demonstrated earlier that estrogen rapidly attenuates nociceptin/orphanin FQ (N/OFQ) peptide receptor (NOP)-mediated thermal antinociception through the activation of membrane estrogen receptors (mERs). However, the effect of mER activation on NOP-mediated attenuation of tactile hypersensitivity in a neuropathic model of pain and the underlying mechanisms remain unknown. Following spared nerve injury (SNI), male and ovariectomized (OVX) female rats were intrathecally (i.t.) injected with a selective mER agonist and nociceptin/orphanin FQ (N/OFQ), the endogenous ligand for NOP, and their effects on paw withdrawal thresholds (PWTs) were tested. In addition, spinal cord tissue was used to measure changes in phosphorylated extracellular signal regulated kinase (ERK), protein kinase A (PKA), protein kinase C (PKC), and protein kinase B (Akt) levels. SNI significantly reduced PWTs in males and OVX females, indicating tactile hypersensitivity. N/OFQ restored PWTs, indicating an antihypersensitive effect. Selective mER activation attenuated the effect of N/OFQ in an antagonist-reversible manner. SNI led to a robust increase in the phosphorylation of ERK, PKA, PKC, and Akt. However, mER activation did not further affect it. Thus, we conclude that activation of mERs rapidly abolishes NOP-mediated tactile antihypersensitivity following SNI via an ERK-, PKA-, PKC-, and Akt-independent mechanism.
Learn More >Migraine is a complex neurovascular disorder with a strong genetic component. There are rare monogenic forms of migraine, as well as more common polygenic forms; research into the genes involved in both types has provided insights into the many contributing genetic factors. This review summarises advances that have been made in the knowledge and understanding of the genes and genetic variations implicated in migraine etiology.
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