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Sensory problems, such as neuropathic pain, are common and debilitating symptoms in multiple sclerosis (MS), an autoimmune inflammatory disorder of the central nervous system (CNS). Regulatory T (Treg) cells are critical for maintaining immune homeostasis, however, their role in MS-associated pain remains unknown. Here, we demonstrate that Treg cell ablation is sufficient to trigger experimental autoimmune encephalomyelitis (EAE) and facial allodynia in immunised female mice. In EAE-induced female mice, adoptive transfer of Treg cells and spinal delivery of the Treg cell cytokine interleukin (IL)-35 significantly reduced facial stimulus-evoked pain and spontaneous pain independent of disease severity, and increased myelination of the facial nociceptive pathway. The effects of intrathecal IL-35 therapy were Treg cell-dependent, and were associated with upregulated IL-10 expression in CNS-infiltrating lymphocytes, and reduced monocyte infiltration in the trigeminal afferent pathway. Taken together, we present evidence for a beneficial role of Treg cells and IL-35 in attenuating pain associated with EAE, independently of motor symptoms, by decreasing neuroinflammation and increasing myelination.Pain is a highly prevalent symptom affecting the majority of multiple sclerosis (MS) patients and dramatically affects overall health-related quality-of-life, yet represents a research area that has been largely ignored. Here we identify, for the first time, a role for regulatory T cells and interleukin-35 in suppressing facial allodynia and facial grimacing in animals with experimental autoimmune encephalomyelitis (EAE). We demonstrate that spinal delivery of regulatory T cells and interleukin-35 reduces pain associated with EAE by decreasing neuroinflammation and increasing myelination, independently of motor symptoms. These findings increase our understanding of the mechanisms underlying pain in EAE, and suggest potential treatment strategies for pain relief in MS.
Learn More >Since noxious stimulation usually leads to the perception of pain, pain has traditionally been considered sensory nociception. But its variability and sensitivity to a broad array of cognitive and motivational factors have meant it is commonly viewed as inherently imprecise and intangibly subjective. However, the core function of pain is motivational-to direct both short- and long-term behavior away from harm. Here, we illustrate that a reinforcement learning model of pain offers a mechanistic understanding of how the brain supports this, illustrating the underlying computational architecture of the pain system. Importantly, it explains why pain is tuned by multiple factors and necessarily supported by a distributed network of brain regions, recasting pain as a precise and objectifiable control signal.
Learn More >Gender disparities in chronic pain are well documented in the literature. However, little is known regarding the relationship between physical activity (PA) and gender disparities in chronic pain. This study described gender differences in prevalence of chronic pain and PA, and identified a type of leisure time PA that individuals frequently chose in a nationally representative sample of US adults ( = 14,449). Data from the National Health Nutrition Examination Survey 1999⁻2004 were analyzed. Individuals were categorized into no chronic pain (NCP), localized chronic pain (LCP), and widespread chronic pain (WCP) groups based on responses to a pain questionnaire. A self-report PA questionnaire was used to estimate the time spent in different types of PA. Women showed higher prevalence of LCP and WCP compared to men. Men spent more hours per week for leisure time PA compared to women, but men and women showed similar prevalence of sufficient PA to meet a PA recommendation (≥150 min/week of moderate-to-vigorous intensity PA) across chronic pain categories. However, the prevalence of sufficient PA was substantially higher among men and women with NCP compared to men and women with LCP and WCP. Additionally, both men and women chose walking as the primary type of leisure time PA. Together, gender disparities exist in the prevalence of chronic pain and hours spent for leisure time PA. More research is needed to explore the role of increasing leisure time PA, such as walking, in reducing gender disparities in chronic pain.
Learn More >The U.S. Advisory Committee on Immunization Practices recently developed recommendations for use of a new recombinant zoster vaccine (RZV).
Learn More >Clinically, osteoarthritis (OA) pain is significantly associated with synovial inflammation. Identification of the mechanisms driving inflammation could reveal new targets to relieve this prevalent pain state. Herein, a role of polyadenylation in OA synovial samples was investigated, and the potential of the polyadenylation inhibitor cordycepin (3' deoxyadenosine) to inhibit inflammation as well as to reduce pain and structural OA progression were studied. Joint tissues from people with OA with high or low grade inflammation and non-arthritic post-mortem controls were analysed for the polyadenylation factor CPSF4 and inflammatory markers. Effects of cordycepin on pain behavior and joint pathology were studied in models of OA (intra-articular injection of monosodium iodoacetate in rats and surgical destabilisation of the medial meniscus in mice). Human monocyte-derived macrophages and a mouse macrophage cell line were used to determine effects of cordycepin on nuclear localisation of the inflammatory transcription factor NFĸB and polyadenylation factors (WDR33 and CPSF4). CPSF4 and NFκB expression were increased in synovia from OA patients with high grade inflammation. Cordycepin reduced pain behaviour, synovial inflammation and joint pathology in both OA models. Stimulation of macrophages induced nuclear localisation of NFĸB and polyadenylation factors, effects inhibited by cordycepin. Knockdown of polyadenylation factors also prevented nuclear localisation of NFĸB. The increased expression of polyadenylation factors in OA synovia indicates a new target for analgesia treatments. This is supported by the finding that polyadenylation factors are required for inflammation in macrophages and by the fact that the polyadenylation inhibitor cordycepin attenuates pain and pathology in models of OA.
Learn More >Complex regional pain syndrome (CRPS) is a debilitating condition where trauma to a limb results in devastating persistent pain that is disproportionate to the initial injury. The pathophysiology of CRPS remains unknown; however, accumulating evidence suggests it is an immunoneurological disorder, especially in light of evidence of auto-antibodies in ~ 30% of patients. Despite this, a systematic assessment of all circulating leukocyte populations in CRPS has never been performed.
Learn More >Self-management interventions are well recognised and widely used in chronic conditions. Their application to chronic headaches has been limited and generally of low quality. We describe here our process for developing an evidence based, and theory driven, education and self-management intervention for those living with chronic headache.
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