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Neuropathic pain (NP) is one of the most common and debilitating comorbidities of spinal cord injury (SCI). Current therapies are often ineffective due in part to an incomplete understanding of underlying pathogenic mechanisms. In particular, it remains unclear how SCI leads to dysfunction in the excitability of nociceptive circuitry. The immediate early gene c-Fos has long been used in pain processing locations as a marker of neuronal activation. We employed a mouse reporter line with fos-promoter driven Cre-recombinase to define neuronal activity changes in relevant pain circuitry locations following C5/6 contusion (using both females and males), a SCI model that results in multiple forms of persistent NP-related behavior. SCI significantly increased activation of cervical dorsal horn (DH) projection neurons, as well as induced a selective reduction in the activation of a specific DH projection neuron subpopulation that innervates the periaqueductal gray (PAG), an important brain region involved in descending inhibitory modulation of DH pain transmission. SCI also increased the activation of both PKCγ and calretinin excitatory DH interneuron populations. Interestingly, SCI promoted a significant decrease in the activation selectively of nNOS expressing inhibitory interneurons of cervical DH. In addition, SCI altered activation of various supraspinal neuron populations associated with pain processing, including a large increase in thalamus and a significant decrease in PAG. These findings reveal a complex and diverse set of SCI-induced neuron activity changes across the pain circuitry neuraxis. Moving forward, these results can be used to inform therapeutic targeting of defined neuronal populations in NP.NP is one of the most common and highly debilitating comorbidities of SCI. Unfortunately, current therapies are often ineffective due in part to an incomplete understanding of underlying pathogenic mechanisms. In particular, it remains unclear how SCI leads to dysfunction in excitability of nociceptive circuitry. Using a FosTRAP2 reporter mouse line in a model of SCI-induced NP, we show SCI alters activation of a number of important interneuron and projection neuron populations across relevant spinal cord and brain locations of the pain circuitry neuraxis. These data suggest a role for maladaptive plasticity involving specific subpopulations of neurons and circuits in driving SCI-induced chronic pain. Moving forward, these results can be used to inform therapeutic targeting of defined neuronal populations in NP.
Learn More >Recurrent pain is an increasing public health problem among school-aged children, with potential negative impact on children´s daily lives, such as schoolwork. The overall aim of this study was to investigate whether recurrent pain in school year 6 was associated with poorer academic achievement at the end of elementary school in school year 9. The study was a follow-up study based on data from "The Study of Health in School-Aged Children from Umeå" (SISU). Participants were 1567 children aged 12 to 13 years who attended school year 6. A follow-up was done in school year 9, when the children were 16 years old. The children answered a questionnaire about recurrent pain (headache, stomachache, and backache). Information about academic achievement was collected from school registers. The results showed that having weekly recurrent pain in school year 6 predicted lower final overall grade points in school year 9 compared to children with no recurrent pain. This applied for recurrent headache, stomachache, backache, and multiple pains and for both girls and boys. Recurrent pain did not predict secondary school eligibility, however. Perceived problems with academic achievement and problems with concentration partly mediated the association between recurrent pain and lower final overall grade points. Sleep problems were not associated with academic achievement and were therefore not a mediator. Thus, the results suggest that recurrent pain may predict later impairment of academic achievement and that problems with concentration and children´s perceived achievement in school, but not sleep problems, may partly explain this relationship.
Learn More >Photobiomodulation therapy (PBM) is often used to treat musculoskeletal disorders such as chronic non-specific low back pain (NSCLBP) as it can have positive effects on biomarkers-creatine kinase (CK) and serum cortisol levels-related to stress caused by physical exercise, such as deep water running (DWR) or by pain. The aim of this study was to evaluate the effects of the combination of PBM and aquatic exercise (DWR) on the intensity of pain, disability, 6-min walk test adapted (6WTA), and on cortisol and creatine kinase (CK) levels in a population with NSCLBP. The participants were allocated into three groups: TG (Photobiomodulation and Training Group), TG (Placebo Photobiomodulation and Training Group), and the G (Photobiomodulation Group). Information regarding anthropometric data, blood pressure, and heart rate were collected, and the questionnaires were applied: IPAQ-Short Form, Oswestry Disability Index, and the Visual Analog Scale for Pain. The submaximal exercise test (6WTA) was performed. Blood was collected for analysis of cortisol and CK levels. The training sessions were performed twice a week, for 4 weeks. In the intragroup comparisons, there were statistically significant changes in the TG and G groups in the outcomes pain intensity, disability (reductions in both groups), and in cortisol (increased in the TG and reduced in the G); in the TG group, there was a statistically significant reduction only in the outcome of pain intensity. In the intergroup comparison, in the comparison between TG and TG, there was a statistically significant difference in the level of cortisol, as well as in the comparison between TG and G, in which there was a statistically significant difference for this same outcome (cortisol) and for the 6WTA outcome. The effects of the combination of PBM and aquatic exercise have positive effects on reducing pain intensity, disability, and cortisol levels, but its effects on other variables (6WTA and CK) are too small to be considered significant. Trial registration number: NCT03465228-April 3, 2019; retrospectively registered (ClinicalTrials.gov).
Learn More >Osteoarthritis is a degenerative disease of the knee that affects 250 million people worldwide. Due to the rising incidence of knee replacement and revision surgery, there is a need for a nonsurgical treatment to reduce pain and improve function in patients with knee osteoarthritis. Placental-derived allografts, such as an amniotic suspension allograft (ASA), provide growth factors and cytokines that could potentially modulate the inflammatory environment of osteoarthritis. The purpose of this study was to evaluate the efficacy of ASA in a rat medial meniscal tear (MMT) induced osteoarthritis model through histology, microCT, synovial fluid biomarkers, and behavioral testing.
Learn More >Brainstem to spinal cord noradrenergic pathways include a locus coeruleus origin projection and diffuse noxious inhibitory controls. While both pathways are traditionally viewed as exerting an inhibitory effect on spinal neuronal activity, the locus coeruleus was previously shown to have a facilitatory influence on thermal nociception according to the subpopulation of coerulean neurons activated. Coupled with knowledge of its functional modular organisation and the fact that diffuse noxious inhibitory controls are not expressed in varied animal models of chronicity, we hypothesised a regulatory role for the locus coeruleus on non-coerulean, discrete noradrenergic cell group(s). We implemented locus coeruleus targeting strategies by microinjecting canine adenovirus encoding for channelrhodopsin-2 under a noradrenaline-specific promoter in the spinal cord (retrogradely labelling a coeruleospinal module) or the locus coeruleus itself (labelling the entire coerulean module). Coeruleospinal module optoactivation abolished diffuse noxious inhibitory controls (Two-Way ANOVA, P < 0.0001), which were still expressed following locus coeruleus neuronal ablation. We propose that the cerulean system interacts with, but does not directly govern, diffuse noxious inhibitory controls. This mechanism may underlie the role of the locus coeruleus as a 'chronic pain generator'. Pinpointing the functionality of discrete top-down pathways is crucial for understanding sensorimotor modulation in health and disease.
Learn More >Burn injury in children can cause severe and chronic physical and mental sequelae. Opioids are a mainstay in burn pain management but increasing utilization in this country has led to concern for their continued use and potential for dependence. Methadone is a long-acting analgesic that targets the N-methyl-D-aspartate (NMDA) receptor in addition to the mu opioid receptor and has benefit in adult burn patients. However, its use in the pediatric burn population has been less robustly studied. This is a retrospective cohort study at a single Level 1 Burn Center whose primary aim is to compare opioid utilization 36 hours postoperatively between pediatric burn patients who received intraoperative, intravenous methadone and those who did not. Secondary aim was to describe differences in methadone-related complications between the cohorts. There was decreased opioid utilization measured by median morphine equivalents per kilogram (ME/kg) postoperatively in the methadone cohort compared to the control cohort (0.54mg/kg v. 0.77mg/kg, p = 0.18). No adverse events were noted upon chart review. The data suggests methadone use is beneficial in pediatric burn patients, but further prospective studies are warranted on a larger population.
Learn More >Itch (pruritus) is a common chronic condition with a lifetime prevalence of over 20%. The mechanisms underlying itch are poorly understood, and its therapy is difficult. There is recent evidence that following nerve injury or inflammation, intercellular communications in sensory ganglia are augmented, which may lead to abnormal neuronal activity, and hence to pain, but there is no information whether such changes take place in an itch model. We studied changes in neurons and satellite glial cells (SGCs) in trigeminal ganglia in an itch model in mice using repeated applications of 2,4,6-trinitro-1-chlorobenzene (TNCB) to the external ear over a period of 11 days. Treated mice showed augmented scratching behavior as compared with controls during the application period and for several days afterwards. Immunostaining for the activation marker glial fibrillary acidic protein in SGCs was greater by about 35% after TNCB application, and gap junction-mediated coupling between neurons increased from about 2% to 13%. The injection of gap junction blockers reduced scratching behavior, suggesting that gap junctions contribute to itch. Calcium imaging studies showed increased responses of SGCs to the pain (and presumed itch) mediator ATP. We conclude that changes in both neurons and SGCs in sensory ganglia may play a role in itch.
Learn More >This review discusses the role of opioids in the corneal surface and the different pathways and therapeutic methods of management. A literature review was performed using PubMed database. For the database search, the main searching words "opioid" and "topical opioid treatment" were used with the descriptors "cornea", "ocular surface", "neuropathic corneal pain", "corneal sensitivity" and "naltrexone"; original scientific articles and reviews were included to achieve the purpose of the review. The endogenous opioid system has relevant functions in the organism, and in daily use, opioids are used as painkillers. However, these drugs may be employed for other indications as opioid pathways have a wide spectrum. The corneal surface for topical treatment is easily accessible, hence sparing the side effects of systemic opioids. Instillation of opioid antagonist substances, such as naltrexone, increases corneal healing rates and stimulates the division of corneal epithelium cells without deleterious effects. The natural modulation of endogenous opioids controls different forms of pain, including inflammatory and neuropathic pain, both in the ocular surface and in the central nervous system. There are diverse methods in controlling pain using opioids, especially in refractory forms. This review attempts to collect the literature about corneal surface and opioid pathways to provide an overview image and a possible direction of the news treatments.
Learn More >Rheumatoid arthritis (RA) is a chronic inflammatory and autoimmune disease characterized by the attack of the immune system on the body's healthy joint lining and degeneration of articular structures. This disease involves an increased release of inflammatory mediators in the affected joint that sensitize sensory neurons and create a positive feedback loop to further enhance their release. Among these mediators, the cytokines and neuropeptides are responsible for the crippling pain and the persistent neurogenic inflammation associated with RA. More importantly, specific proteins released either centrally or peripherally have been shown to play opposing roles in the pathogenesis of this disease: an inflammatory role that mediates and increases the severity of inflammatory response and/or an anti-inflammatory and protective role that modulates the process of inflammation. In this review, we will shed light on the neuroimmune function of different members of the heat shock protein (HSPs) family and the complex manifold actions that they exert during the course of RA. Specifically, we will focus our discussion on the duality in the mechanism of action of Hsp27, Hsp60, Hsp70, and Hsp90.
Learn More >Post-traumatic trigeminal neuropathy (PTTN) is a chronic sensory disorder that afflicts patients with nerve injury caused by orofacial and dental surgery or cervicofacial trauma. Currently, effective treatment strategies for PTTN are lacking, and patients treated with conventional drugs for PTTN experience adverse effects such as drowsiness and drug addiction. In the present study, we investigated whether mirogabalin, a novel gabapentinoid, could be an effective treatment for PTTN induced by distal infraorbital nerve chronic constriction injury (dIoN-CCI) in the mouse. Increased facial grooming time and hyper-responsiveness to acetone were observed in dIoN-CCI mice. These pain-related behaviors were attenuated by intraperitoneal injection of mirogabalin. In particular, mirogabalin significantly diminished the increase in facial grooming time. The analgesic effect of mirogabalin injection started 45minutes after the injection and persisted for 6hours. Additionally, 10mg/kg mirogabalin did not affect locomotor activity in the open field test, suggesting that it does not cause sedation. Together, the current findings suggest that mirogabalin could be a valuable therapeutic drug for PTTN following orofacial surgeries without sedative side effects.
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