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Despite the development of effective therapies, a substantial proportion of asthmatics continue to have uncontrolled symptoms, airflow limitation, and exacerbations. Transient receptor potential cation channel member A1 (TRPA1) agonists are elevated in human asthmatic airways, and in rodents, TRPA1 is involved in the induction of airway inflammation and hyperreactivity. Here, the discovery and early clinical development of GDC-0334, a highly potent, selective, and orally bioavailable TRPA1 antagonist, is described. GDC-0334 inhibited TRPA1 function on airway smooth muscle and sensory neurons, decreasing edema, dermal blood flow (DBF), cough, and allergic airway inflammation in several preclinical species. In a healthy volunteer Phase 1 study, treatment with GDC-0334 reduced TRPA1 agonist-induced DBF, pain, and itch, demonstrating GDC-0334 target engagement in humans. These data provide therapeutic rationale for evaluating TRPA1 inhibition as a clinical therapy for asthma.
Learn More >Chronic pain-related sickness absence is an enormous socioeconomic burden globally. Optimized interventions are reliant on a lucid understanding of the distribution of social insurance benefits and their predictors. This register-based observational study analyzed data for a seven-year period from a population-based sample of 44,241 chronic pain patients eligible for interdisciplinary treatment (IDT) at specialist clinics. Sequence analysis was used to describe the sickness absence over the complete period and to separate the patients into subgroups based on their social insurance benefits over the final two years. The predictive performance of features from various domains was then explored with machine learning-based modeling in a nested cross-validation procedure. Our results showed that patients on sickness absence increased from 17% five years before to 48% at the time of the IDT assessment, and then decreased to 38% at the end of follow-up. Patients were divided into three classes characterized by low sickness absence, sick leave, and disability pension, with eight predictors of class membership being identified. Sickness absence history was the strongest predictor of future sickness absence, while other predictors included a 2008 policy, age, confidence in recovery, and geographical location. Information on these features could guide personalized intervention in the specialized healthcare. PERSPECTIVE: This study describes sickness absence in patients who visited a Swedish pain specialist interdisciplinary treatment clinic during the period 2005-2016. Predictors of future sickness absence are also identified that should be considered when adapting IDT programs to the patient's needs.
Learn More >Adverse life events (ALEs) are a risk factor for chronic pain; however, mechanisms underlying this association are not understood. This study examined whether cumulative ALE exposure impairs endogenous inhibition of pain (assessed from pain report) and spinal nociception (assessed from nociceptive flexion reflex; NFR) in healthy, pain-free Native Americans (n=124) and non-Hispanic Whites (n=129) during a conditioned pain modulation (CPM) task. Cumulative ALE exposure was assessed prior to testing by summing the number of potentially traumatic events experienced by each participant across their lifespan. Multilevel modeling found that ALEs were associated with NFR modulation during the CPM task even after controlling for general health, body mass index, sex, age, blood pressure, sleep quality, stimulation intensity, stimulus number, perceived stress, and psychological distress. Low exposure to ALEs was associated with NFR inhibition, whereas high exposure to ALEs was associated with NFR facilitation. By contrast, pain perception was inhibited during the CPM task regardless of the level of ALE exposure. Race/ethnicity did not moderate these results. Thus, ALEs may be pronociceptive for both Native Americans and non-Hispanic Whites by impairing descending inhibition of spinal nociception. This could contribute to a chronic pain risk phenotype involving latent spinal sensitization. Perspective: This study found that adverse life events were associated with impaired descending inhibition of spinal nociception in a sample of Native Americans and non-Hispanic Whites. These findings expand on previous research linking adversity to chronic pain risk by identifying a proximate physiological mechanism for this association.
Learn More >Migraine sufferers often exhibit photophobia and physical hypoactivity in the postdrome and interictal periods, for which no effective therapy currently exists. Cortical spreading depolarization (CSD) is a neural phenomenon underlying migraine aura. We previously reported that CSD induced trigeminal sensitization, photophobia, and hypomobility at 24 h in mice. Here, we examined the effects of CSD induction on light sensitivity and physical activity in mice at 48 h and 72 h. Trigeminal sensitization was absent at both time points. CSD-subjected mice exhibited significantly less ambulatory time in both light (P = 0.0074, the Bonferroni test) and dark (P = 0.0354, the Bonferroni test) zones than sham-operated mice at 72 h. CSD-subjected mice also exhibited a significantly shorter ambulatory distance in the light zone at 72 h than sham-operated mice (P = 0.0151, the Bonferroni test). Neurotropin® is used for the management of chronic pain disorders, mainly in Asian countries. The CSD-induced reductions in ambulatory time and distance in the light zone at 72 h were reversed by Neurotropin® at 0.27 NU/kg. Our experimental model seems to recapitulate migraine-associated clinical features observed in the postdrome and interictal periods. Moreover, Neurotropin® may be effective in ameliorating postdromal/interictal hypoactivity, especially in a light environment.
Learn More >IL-31 is a major pruritogen associated with atopic dermatitis (AD). Although a specific antibody for IL-31 receptor has been shown to alleviate pruritus in patients with AD, therapeutic approaches to inhibit IL-31 production remain unexploited. IL-31 production by helper T cells critically depends on the transcription factor EPAS1, which mediates IL31 promoter activation in collaboration with SP1.
Learn More >Limited understanding of pruritus mechanisms in cholestatic liver diseases hinders development of anti-pruritic treatments. Previous studies implicated lysophosphatidic acid (LPA) as a potential mediator of cholestatic pruritus.
Learn More >The objective of this review of the literature is to summarize the physiology of orofacial pain in dentistry, particularly physiology of the pain pathway and molecular mechanisms on pathophysiology of pain, on account of new insights into classification of orofacial pain related diseases. This article will also focus on possible mechanisms of neuropathic orofacial pain which is distinguished from other pain types.
Learn More >Peripheral sensory neurons transduce physicochemical stimuli affecting somatic tissues into the firing of action potentials that are conveyed to the central nervous system. This results in conscious perception, adaptation, and survival, but alterations of the firing patterns can result in pain and hypersensitivity conditions. Thus, understanding the molecular mechanisms underlying action potential firing in peripheral sensory neurons is essential in sensory biology and pathophysiology. Over the past 30 years, it has been consistently reported that these cells can display membrane potential instabilities (MPIs), in the form of subthreshold membrane potential oscillations or depolarizing spontaneous fluctuations. However, research on this subject remains sparse, without a clear conductive thread to be followed. To address this, we here provide a synthesis of the description, molecular bases, mathematical models, physiological roles, and pathophysiological implications of MPIs in peripheral sensory neurons. Membrane potential instabilities have been reported in trigeminal, dorsal root, and Mes-V ganglia, where they are believed to support repetitive firing. They are proposed to have roles also in intercellular communication, ectopic firing, and responses to tonic and slow natural stimuli. We highlight how MPIs are of great interest for the study of sensory transduction physiology and how they may represent therapeutic targets for many pathological conditions, such as acute and chronic pain, itch, and altered sensory perceptions. We identify future research directions, including the elucidation of the underlying molecular determinants and modulation mechanisms, their relation to the encoding of natural stimuli and their implication in pain and hypersensitivity conditions.
Learn More >The novel coronavirus disease (COVID-19) has caused prolonged disruptions in daily life for many communities. Little is known about the impact of the COVID-19 pandemic on the health and well-being of youth with chronic pain and their families. We conducted a longitudinal, mixed-methods study to characterize early adaptation to the COVID-19 pandemic among 250 families of youth (ages 12-21 years) diagnosed with chronic headache (64%) or other chronic pain conditions (36%) and to determine whether direct exposures to COVID-19 and secondary economic stress modified symptom trajectories. Youth and parents reported on pain interference, anxiety, depression, and insomnia symptoms at 4 waves of data collection from April 2020 to July 2020. We also collected qualitative data on the impact of the pandemic on the youth's pain problem. Nearly half of our sample (49.6%) experienced direct exposures to COVID-19. Secondary economic stress was also common, affecting 44.4% of families. Symptom trajectories for pain, insomnia, depression, and anxiety remained stable or improved for most participants, indicating adaptive adjustment. However, overall symptom burden was high with persistent and clinically elevated depression, anxiety, and insomnia symptoms common among youth and parents. Direct exposures to COVID-19 did not modify symptom trajectories. However, youth pain interference and parent insomnia worsened in families who experienced secondary economic stress. Qualitative data revealed perceived benefits and harms from school closures on the youth's pain problem. Our findings of high symptom burden suggest that pediatric pain clinicians should offer distance assessment and treatment (eg, through telemedicine) to avoid pandemic-related disruptions in pain care.
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