The journal of pain : official journal of the American Pain Society
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Deactivation of the medial prefrontal cortex (mPFC) has been broadly reported in both neuropathic pain models and human chronic pain patients. Several cellular mechanisms may contribute to the inhibition of mPFC activity, including enhanced GABAergic inhibition. The functional effect of GABAA(γ-aminobutyric acid type A)-receptor activation depends on the concentration of intracellular chloride in the postsynaptic neuron, which is mainly regulated by the activity of Na-K-2Cl cotransporter isoform 1 (NKCC1) and K-Cl cotransporter isoform 2 (KCC2), 2 potassium-chloride cotransporters that import and extrude chloride, respectively. ⋯ PERSPECTIVE: Chronic pain is associated with the presence of depolarizing GABAA current in the spinal cord, suggesting that pharmacological NKCC1 antagonism has analgesic effects. However, our results show that in neuropathic pain, GABAA current is actually hyperinhibitory in the mPFC, where it contributes to the mPFC functional deactivation. This suggests caution in the use of NKCC1 antagonism to treat pain.
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Neuropathic screening tools improve recognition of neuropathic pain in adults. Although utilized in pediatric populations, the sensitivity, specificity and methodology of screening tool delivery have not been compared in children. We evaluated the Self-Report Leeds Assessment of Neuropathic Symptoms and Signs (S-LANSS) in adolescents (10-18 years) referred to a tertiary pediatric pain clinic. ⋯ The S-LANSS is a sensitive screening tool for pain with neuropathic features in adolescents, but needs to be interpreted in the context of clinical evaluation (clinicaltrials.gov NCT03312881). PERSPECTIVE: This article reports high sensitivity of the S-LANSS screening tool for identifying pain with neuropathic features in adolescents with moderate-severe chronic pain. However, as sensitivity is lower than in adult populations, further interdisciplinary evaluation is necessary to inform diagnosis and management.
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Despite known health disparities in chronic pain conditions between rural and urban adults, few studies have examined whether longitudinal associations between psychological stress and hand pain differ. Utilizing community-based cohort data, this study examined whether rural and urban adults differed in the extent to which psychological distress was associated with hand osteoarthritis (OA) symptoms and later functional limitations related to hand pain. Community-dwelling adults (mean age = 51.97, 52.3% women) in a rural (n = 2,971) and urban area (n = 2,782) provided demographic data at baseline and, at a 4-year follow-up, responded to questionnaires about psychological distress and clinical symptoms of hand OA. ⋯ There was significant moderation by residential area, such that the association between psychological distress and hand OA was significant only among rural adults and the association with functional limitations was stronger in rural adults than urban adults. Findings suggest greater vulnerability to hand arthritis and hand-related functional limitations among rural adults and the potential for tailored intervention programs to help resolve health disparities among rural communities. PERSPECTIVE: This study compares the association between psychological distress and hand pain outcomes between rural and urban adults using community-based cohort data and suggests that rural adults are more vulnerable to experiencing negative effects of psychological distress on concurrent hand OA symptoms and longitudinal functional limitations in hands.
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Identifying and resolving molecular complexities underlying chronic neuropathic pain is a significant challenge. Among the numerous classes of histone deacetylases, Class I (HDAC 1-3) and Class III (sirtuins) have been best studied in experimental pain models where inhibitor pre-treatments but not post-treatments abrogate the development of pain-related behaviors. Post-treatment here in week 3 with less well-studied Class IIa HDAC4/5 selective inhibitor LMK235 diminishes the trigeminal ganglia increases of HDAC5 RNA and protein in two chronic orofacial neuropathic pain models to levels measured in naïve mice at week 10 post-model induction. ⋯ LMK235 reverses long-standing mechanical and cold hypersensitivity in chronic trigeminal neuropathic pain models in males and females (5,10 mg/kg), preventing development of anxiety- and depression-like behaviors. PERSPECTIVE: Data here support HDAC5 as key epigenetic factor in chronic trigeminal neuropathic pain persistence, validated with the study of RNA alterations, TG neuronal excitability, and pain-related behaviors. HDAC5 inhibitor given in week 3 restores RNA balance at 10 weeks, while upregulation remains for response to wound healing and chronic inflammation RNAs.
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Trigeminal neuralgia is a heterogeneous disorder with likely multifactorial and complex etiology; however, trigeminal nerve demyelination and injury are observed in almost all patients with trigeminal neuralgia. The current management strategies for trigeminal neuralgia primarily involve anticonvulsants and surgical interventions, neither of which directly address demyelination, the pathological hallmark of trigeminal neuralgia, and treatments targeting demyelination are not available. Demyelination of the trigeminal nerve has been historically considered a secondary effect of vascular compression, and as a result, trigeminal neuralgia is not recognized nor treated as a primary demyelinating disorder. ⋯ PERSPECTIVE: This article proposes trigeminal neuralgia as a demyelinating disease, supported by histological, clinical, and radiological evidence. Such categorization offers a plausible explanation for controversies surrounding trigeminal neuralgia. This perspective holds potential for future research and developing therapeutics targeting demyelination in the condition.