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Sleep loss increases the experience of pain. However, the brain mechanisms underlying altered pain processing following sleep deprivation are unknown. Moreover, it remains unclear whether ecologically modest night-to-night changes in sleep, within an individual, confer consequential day-to-day changes in experienced pain. Here, we demonstrate that acute sleep-deprivation amplifies pain reactivity within human (male and female) primary somatosensory cortex yet blunts pain-reactivity in higher-order valuation and decision-making regions of the striatum and insula cortex. Consistent with this altered neural signature, we further show that sleep deprivation expands the temperature range for classifying a stimulus as painful, specifically through a lowering of pain thresholds. Moreover, the degree of amplified reactivity within somatosensory cortex following sleep deprivation significantly predicts this expansion of experienced pain across individuals. Finally, outside of the laboratory setting, we similarly show that even modest nightly changes in sleep quality (increases and decreases) an individual determine consequential day-to-day changes in experienced pain (decreases and increases, respectively). Together, these data provide a central brain framework underlying the impact of sleep loss on pain, and furthermore, establish that the association between sleep and pain is expressed in a night-to-day, bidirectional relationship within a sample of the general population. More broadly, our findings highlight sleep as a novel therapeutic target for pain management within and outside the clinic, including circumstances where sleep is frequently short yet pain is abundant (e.g. the hospital setting).Are you experiencing pain? Did you have a bad night of sleep? This study provides underlying brain and behavioral mechanisms explaining this common co-occurrence. We show that sleep deprivation enhances pain responsivity within the primary sensing regions of the brain's cortex yet blunts activity in other regions that modulate pain processing-the striatum and insula. We further establish that even subtle night-to-night changes in sleep in a sample of the general population predict consequential day-to-day changes in pain (bidirectionally). Considering the societal rise in chronic pain conditions in lock-step with the decline in sleep time through the industrial world, our data support the hypothesis that these two trends may not simply be co-occurring but are significantly inter-related.
Learn More >Gastrin-releasing peptide (GRP) is a spinal itch transmitter expressed by a small population of dorsal horn interneurons (GRP neurons). The contribution of these neurons to spinal itch relay is still only incompletely understood and their potential contribution to pain-related behaviors remains controversial. Here, we have addressed this question in a series of experiments performed in GRP::cre and GRP::eGFP transgenic male mice. We combined behavioral tests with neuronal circuit tracing, morphology, chemogenetics, optogenetics, and electrophysiology to obtain a more comprehensive picture. We found that GRP neurons form a rather homogenous population of central cell-like excitatory neurons located in lamina II of the superficial dorsal horn. Multicolor high-resolution confocal microscopy and optogenetic experiments demonstrated that GRP neurons receive direct input from MrgprA3-positive pruritoceptors. Anterograde herpes simplex virus-based neuronal tracing initiated from GRP neurons revealed ascending polysynaptic projections to distinct areas and nuclei in the brainstem, midbrain, thalamus, and the somatosensory cortex. Spinally restricted ablation of GRP neurons reduced itch-related behaviors to different pruritogens while their chemogenetic excitation elicited itch-like behaviors and facilitated responses to several pruritogens. By contrast, responses to painful stimuli remained unaltered. These data confirm a critical role of dorsal horn GRP neurons in spinal itch transmission, but do not support a role in pain. Dorsal horn GRP neurons serve a well-established function in the spinal transmission of pruritic (itch) signals. A potential role in the transmission of nociceptive (pain) signals has remained controversial. Our results provide further support for a critical role of dorsal horn GRP neurons in itch circuits, but we failed to find evidence supporting a role in pain.
Learn More >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.
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