Schwann cells modulate nociception in neurofibromatosis 1.

Pain of unknown etiology is frequent in individuals with the tumor predisposition syndrome neurofibromatosis 1 (NF1), even when tumors are absent. Nerve Schwann cells (SCs) were recently shown to play roles in nociceptive processing, and we find that chemogenetic activation of SCs is sufficient to induce afferent and behavioral mechanical hypersensitivity in wild-type mice. In mouse models, animals showed afferent and behavioral hypersensitivity when SCs, but not neurons, lacked Nf1. Importantly, hypersensitivity corresponded with SC-specific upregulation of mRNA encoding glial cell line-derived neurotrophic factor (GDNF), independently of the presence of tumors. Neuropathic pain-like behaviors in the NF1 mice were inhibited by either chemogenetic silencing of SC calcium or by systemic delivery of GDNF-targeting antibodies. Together, these findings suggest that alterations in SCs directly modulate mechanical pain and suggest cell-specific treatment strategies to ameliorate pain in individuals with NF1.

Genetic and epigenetic mechanisms influencing acute to chronic postsurgical pain transitions in pediatrics: Preclinical to clinical evidence.

Background: Chronic postsurgical pain (CPSP) in children remains an important problem with no effective preventive or therapeutic strategies. Recently, genomic underpinnings explaining additional interindividual risk beyond psychological factors have been proposed. Aims: We present a comprehensive review of current preclinical and clinical evidence for genetic and epigenetic mechanisms relevant to pediatric CPSP. Methods: Narrative review. Results: Animal models are relevant to translational research for unraveling genomic mechanisms. For example, Cacng2, p2rx7, and bdnf mutant mice show altered mechanical hypersensitivity to injury, and variants of the same genes have been associated with CPSP susceptibility in humans; similarly, differential DNA methylation (H1SP) and miRNAs (miR-96/7a) have shown translational implications. Animal studies also suggest that crosstalk between neurons and immune cells may be involved in nociceptive priming observed in neonates. In children, differential DNA methylation in regulatory genomic regions enriching GABAergic, dopaminergic, and immune pathways, as well as polygenic risk scores for enhanced prediction of CPSP, have been described. Genome-wide studies in pediatric CPSP are scarce, but pathways identified by adult gene association studies point to potential common mechanisms. Conclusions: Bench-to-bedside genomics research in pediatric CPSP is currently limited. Reverse translational approaches, use of other -omics, and inclusion of pediatric/CPSP endophenotypes in large-scale biobanks may be potential solutions. Time of developmental vulnerability and longitudinal genomic changes after surgery warrant further investigation. Emergence of promising precision pain management strategies based on gene editing and epigenetic programing emphasize need for further research in pediatric CPSP-related genomics.

Contexte: La douleur chronique post-chirurgicale (DCPC) chez l'enfant reste un problème important pour lequel il n'y a pas de stratégies préventives ou thérapeutiques efficaces. Récemment, des fondements génomiques expliquant des risques interindividuels additionnels, au-delà des facteurs psychologiques, ont été proposés. Objectifs: Nous présentons une revue compléte des données probantes précliniques et cliniques actuelles pour les mécanismes génétiques et épigénétiques pertinents en matiére de DCPC pédiatrique. Méthodes: Revue narrative.Les modéles animaux sont pertinents pour la recherche translationnelle afin de déchiffrer les mécanismes génomiques. Par exemple, les souris mutantes Cacng2, p2rx7 et bdnf présentent une hypersensibilité mécanique altérée à des lésions et des variantes des mêmes génes ont été associées à la sensibilité à la DCPC chez l'humain; de même, la méthylation différentielle de l'ADN (H1SP) et les miARN (miR-96/7a) ont montré des implications translationnelles. Des études menées sur des animaux indiquent également que la diaphonie entre les neurones et les cellules immunitaires peut être impliquée dans l'amorçage nociceptif observé chez les nouveau-nés. Chez les enfants, la méthylation différentielle de l'ADN dans les régions génomiques régulatrices enrichissant les voies GABAergiques, dopaminergiques et immunitaires, ainsi que des scores de risque polygénique pour une prédiction améliorée de la PCSP, ont été décrits. Les études pangénomiques en matiére de DCPC pédiatrique sont rares, mais les voies identifiées par les études d'association de génes chez l'adulte indiquent de possibles mécanismes communs. Conclusions: La recherche en génomique du laboratoire au patient dans le cadre de la DCPC pédiatrique est actuellement limitée. Les approches translationnelles inversées, l'utilisation d'autres -omiques et l'inclusion d'endophénotypes pédiatriques/DCPC dans les biobanques à grande échelle peuvent être des solutions possibles. La durée de la vulnérabilité développementale et des changements génomiques longitudinaux aprés la chirurgie justifie des recherches plus approfondies. L'émergence de stratégies de précision prometteuses basées sur lé'dition de génes et la programmation épigénétique pour la prise en charge de la douleur font valoir la nécessité de poursuivre les recherches sur la génomique pédiatrique liée à la DCPC.

Sigma-1 receptors and progesterone metabolizing enzymes in nociceptive sensory neurons of the female rat trigeminal ganglia: A neural substrate for the antinociceptive actions of progesterone.

Orofacial pain disorders are predominately experienced by women. Progesterone, a major ovarian hormone, is neuroprotective and antinociceptive. We recently reported that progesterone attenuates estrogen-exacerbated orofacial pain behaviors, yet it remains unclear what anatomical substrate underlies progesterone's activity in the trigeminal system. Progesterone has been reported to exert protective effects through actions at intracellular progesterone receptors (iPR), membrane-progesterone receptors (mPR), or sigma 1 receptors (Sig-1R). Of these, the iPR and Sig-1R have been reported to have a role in pain. Progesterone can also have antinociceptive effects through its metabolite, allopregnanolone. Two enzymes, 5α-reductase and 3α-hydroxysteroid dehydrogenase (3α-HSD), are required for the metabolism of progesterone to allopregnanolone. Both progesterone and allopregnanolone rapidly attenuate pain sensitivity, implicating action of either progesterone at Sig-1R and/or conversion to allopregnanolone which targets GABAA receptors. In the present study, we investigated whether Sig-1 Rs are expressed in nociceptors within the trigeminal ganglia of cycling female rats and whether the two enzymes required for progesterone metabolism to allopregnanolone, 5α-reductase and 3α-hydroxysteroid dehydrogenase, are also present. Adult female rats from each stage of the estrous cycle were rapidly decapitated and the trigeminal ganglia collected. Trigeminal ganglia were processed by either fluorescent immunochemistry or western blotting to for visualization and quantification of Sig-1R, 5α-reductase, and 3α-hydroxysteroid dehydrogenase. Here we report that Sig-1Rs and both enzymes involved in progesterone metabolism are highly expressed in a variety of nociceptive sensory neuron populations in the female rat trigeminal ganglia at similar levels across the four stages of the estrous cycle. These data indicate that trigeminal sensory neurons are an anatomical substrate for the reported antinociceptive activity of progesterone via Sig-1R and/or conversion to allopregnanolone.

Regulation of Small GTPase Prenylation in the Nervous System.

Mevalonate pathway inhibitors have been extensively studied for their roles in cholesterol depletion and for inhibiting the prenylation and activation of various proteins. Inhibition of protein prenylation has potential therapeutic uses against neurological disorders, like neural cancers, neurodegeneration, and neurotramatic lesions. Protection against neurodegeneration and promotion of neuronal regeneration is regulated in large part by Ras superfamily small guanosine triphosphatases (GTPases), particularly the Ras, Rho, and Rab subfamilies. These proteins are prenylated to target them to cellular membranes. Prenylation can be specifically inhibited through altering the function of enzymes of the mevalonate pathway necessary for isoprenoid production and attachment to target proteins to elicit a variety of effects on neural cells. However, this approach does not address how prenylation affects a specific protein. This review focuses on the regulation of small GTPase prenylation, the different techniques to inhibit prenylation, and how this inhibition has affected neural cell processes.

Dysphagia: Interprofessional Management, Impact, and Patient-Centered Care.

Dysphagia affects a multitude of people worldwide with tremendous impact on the affected individual, families, and caregivers. Understanding dysphagia, as well as the status of screening, evaluation, and treatment, aids in the knowledge required by a interprofessional team to holistically care for patients with dysphagia and their caregivers. The impact of dysphagia includes potential associated risk and a cascade of effects. Conversations regarding meeting nutrition and fluid needs with consideration for quality of life need to be integrated into the plan of care for individuals with dysphagia.

Rehabilitation Outcomes in Spinal Abscess Patients With and Without a History of Intravenous Substance Abuse.

OBJECTIVE: The aim of the study was to compare functional outcomes of acute inpatient rehabilitation for spinal epidural abscess patients with and without history of intravenous substance abuse. DESIGN: This is a retrospective case series study in freestanding rehabilitation hospital. METHODS: Charts of 28 spinal epidural abscess patients admitted from January 2012 to September 2015: 13 with intravenous substance abuse and 15 without intravenous substance abuse were reviewed. Both groups received standard-of-care rehabilitation. Statistical analyses of Functional Independence Measure scores were conducted using individual 2 (substance use) × 2 (rehabilitation status) repeated measures analysis of variance. Functional outcomes were defined by total Functional Independence Measure scores as well as motor and cognitive subsets. Length of stay and morphine equivalents were also compared. RESULTS: There were no significant differences between the two groups. There was a significant main effect of treatment on total Functional Independence Measure scores (P < 0.001), Functional Independence Measure motor scores (P < 0.001), and Functional Independence Measure cognitive scores (P < 0.01) from admission to discharge. Subsequent Student's t tests revealed that the scores of both groups significantly improved on all Functional Independence Measure components. There were no group differences on length of stay and morphine equivalents at discharge. CONCLUSIONS: Acute inpatient rehabilitation can effectively improve functional outcomes in spinal epidural abscess patients with or without intravenous substance abuse, even though these two patient groups can vary in clinical factors.