Spinal interleukin-6 contributes to central sensitisation and persistent pain hypersensitivity in a model of juvenile idiopathic arthritis

Pain is the most debilitating symptom in juvenile idiopathic arthritis. As pain correlates poorly to the extent of joint pathology, therapies that control joint inflammation are often inadequate as analgesics. We test the hypothesis that juvenile joint inflammation leads to sensitisation of nociceptive circuits in the central nervous system, which is maintained by cytokine expression in the spinal cord. Here, transient joint inflammation was induced in postnatal day (P)21 and P40 male Sprague-Dawley rats with a single intra-articular ankle injection of complete Freund's adjuvant. Hindpaw mechanical pain sensitivity was assessed using von Frey hair and weight bearing tests. Spinal neuron activity was measured using in vivo extracellular recording and immunohistochemistry. Joint and spinal dorsal horn TNFα, IL1β and IL6 protein expression was quantified using western blotting. We observed greater mechanical hyperalgesia following joint inflammation in P21 compared to P40 rats, despite comparable duration of swelling and joint inflammatory cytokine levels. This is mirrored by spinal neuron hypersensitivity, which also outlasted the duration of active joint inflammation. The cytokine profile in the spinal cord differed at the two ages: prolonged upregulation of spinal IL6 was observed in P21, but not P40 rats. Finally, spinal application of anti-IL-6 antibody (30 ng) reduced the mechanical hyperalgesia and neuronal activation. Our results indicate that persistent upregulation of pro-inflammatory cytokines in the spinal dorsal horn is associated with neuronal sensitisation and mechanical hyperalgesia in juvenile rats, beyond the progress of joint pathology. In addition, we provide proof of concept that spinal IL6 is a key target for treating persistent pain in JIA

The pain trajectory of juvenile idiopathic arthritis (JIA): translating from adolescent patient report to behavioural sensitivity in a juvenile animal model

Background: While pain is a common symptom in JIA patients, it remains unclear why some JIA patients develop ongoing or persistent pain. Complex clinical and social settings confound analysis of individual factors that may contribute to this pain. To address this, we first undertook a retrospective analysis of pain reports in a JIA patient cohort with the aim of identifying potential factors contributing to persistent pain. We then carried out an experimental laboratory study, using joint inflammatory pain behaviour in rodents, to validate the role of these factors in the onset of persistent pain under controlled conditions. Methods: Patients: Retrospective analysis of anonymised pain visual analogue scale (VAS) scores and accompanying clinical scores from 97 JIA patients aged 13–19 (mean: 16.40 ± 1.21) collected over 50 weeks. Rats: Experimental study of pain behaviour following intra-articular microinjection of complete Freund’s adjuvant (CFA) in adolescents (n = 25) and young adults (n = 43). Some animals (n = 21) had been previously exposed to joint inflammation in infancy or adolescence. Results: Patients: Cluster analysis of patient pain VAS scores revealed three trajectories over 50 weeks: consistently low pain (n = 45), variable pain (n = 30) and persistently high pain (n = 22). Number of actively inflamed joints did not differ in the three groups. High pain at a single visit correlated with greater physician global assessment of disease activity, while a high pain trajectory over 50 weeks was associated with more limited joints but fewer actively inflamed joints. Rats: Rodents administered ankle joint CFA also exhibit low, medium and high joint pain sensitivities, independent of joint inflammation. Prolonged inflammatory pain behaviour was associated with high background pain sensitivity, following joint inflammation at an earlier stage in life. Conclusions: Both JIA patients and rodents differ in their individual pain sensitivity independent of the concurrent joint inflammation. Using experimental animal models allows us to isolate physiological factors underlying these differences, independently of social or clinical factors. The results suggest that a history of prior arthritic activity/joint inflammation may contribute to high pain sensitivity in adolescents with JIA

Intra-arterial nitroglycerin as directed acute treatment in experimental ischemic stroke

BACKGROUND: Nitroglycerin (also known as glyceryl trinitrate (GTN)), a vasodilator best known for treatment of ischemic heart disease, has also been investigated for its potential therapeutic benefit in ischemic stroke. The completed Efficacy of Nitric Oxide in Stroke trial suggested that GTN has therapeutic benefit with acute (within 6 hours) transdermal systemic sustained release therapy. OBJECTIVE: To examine an alternative use of GTN as an acute therapy for ischemic stroke following successful recanalization. METHODS: We administered GTN IA following transient middle cerebral artery occlusion in mice. Because no standard dose of GTN is available following emergent large vessel occlusion, we performed a dose-response (3.12, 6.25, 12.5, and 25 µg/µL) analysis. Next, we looked at blood perfusion (flow) through the middle cerebral artery using laser Doppler flowmetry. Functional outcomes, including forced motor movement rotor rod, were assessed in the 3.12, 6.25, and 12.5 µg/µL groups. Histological analysis was performed using cresyl violet for infarct volume, and glial fibrillary activating protein (GFAP) and NeuN immunohistochemistry for astrocyte activation and mature neuron survival, respectively. RESULTS: Overall, we found that acute post-stroke IA GTN had little effect on vessel dilatation after 15 min. Functional analysis showed a significant difference between GTN (3.12 and 6.25 µg/µL) and control at post-stroke day 1. Histological measures showed a significant reduction in infarct volume and GFAP immunoreactivity and a significant increase in NeuN. CONCLUSIONS: These results demonstrate that acute IA GTN is neuroprotective in experimental ischemic stroke and warrants further study as a potentially new stroke therapy

Abstract 17689: Distal Ventricular Pacing for Drug-Refractory Mid-Cavity Obstructive Hypertrophic Cardiomyopathy: A Randomized, Placebo-Controlled Trial of Personalized Pacing

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