Pain
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The bladder wall is innervated by a complex network of afferent nerves that detect bladder stretch during filling. Sensory signals, generated in response to distension, are relayed to the spinal cord and brain to evoke physiological and painful sensations and regulate urine storage and voiding. Hyperexcitability of these sensory pathways is a key component in the development of chronic bladder hypersensitivity disorders including interstitial cystitis/bladder pain syndrome and overactive bladder syndrome. ⋯ Further evaluation revealed that Ca V 3.2 blockers significantly inhibited both low- and high-threshold afferents, decreasing peak responses to distension, and delayed activation thresholds, thereby attenuating bladder afferent responses to both physiological and noxious distension. Nocifensive visceromotor responses to noxious bladder distension in vivo were also significantly reduced by inhibition of Ca V 3 with TTA-A2. Together, these data provide evidence of a major role for Ca V 3.2 in regulating bladder afferent responses to bladder distension and nociceptive signalling to the spinal cord.
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A multisystem phenotype with the Triad of bodily pain, psychological distress, and sleep disturbance was found to have high risk for developing initial onset of painful temporomandibular disorders (TMDs) in the multicenter Orofacial Pain: Prospective Evaluation and Risk Assessment dataset. In this study, we systemically examined phenotypic characteristics and explored potential pathophysiology in quantitative sensory testing and autonomic nervous system domains in this multisystem Triad phenotype. Secondary analysis was performed on 1199 non-Triad and 154 Triad TMD-free Orofacial Pain: Prospective Evaluation and Risk Assessment enrollees at baseline. ⋯ These findings highlight the importance of whole-person multisystem assessment at the stage before developing complex pain conditions, such as TMDs, and suggest that, in addition to a "tissue damage monitor," pain should be considered in a broader context, such as a component within a "distress monitoring system" at the whole-person level when multisystem issues copresent. Therefore, the presence or absence of multisystem issues may carry critical information when searching for disease mechanisms and developing mechanism-based intervention and prevention strategies for TMDs and related pain conditions. Cardiovascular autonomic function should be further researched when multisystem issues copresent before developing TMDs.
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The nucleus of the solitary tract (NTS) contains pro-opiomelanocortin (POMC) neurons that are 1 of the 2 major sources of β-endorphin in the brain. The functional role of these NTS POMC neurons in nociceptive and cardiorespiratory function is debated. We have shown that NTS POMC optogenetic activation produces bradycardia and transient apnoea in a working heart-brainstem preparation and chemogenetic activation with an engineered ion channel (PSAM) produced opioidergic analgesia in vivo. ⋯ Inhibiting NTS POMC neurons does not produce any effect on basal nociception but inhibits stress-induced analgesia (unlike inhibition of arcuate POMC neurons). Activation of NTS POMC neuronal populations in conscious mice did not cause respiratory depression, anxiety, or locomotor deficit (in open field) or affective preference. These findings indicate that NTS POMC neurons play a key role in the generation of endorphinergic endogenous analgesia and can also regulate cardiorespiratory function.
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Randomized Controlled Trial
Dose-response relationship and effect modifier of stabilisation exercises in nonspecific low back pain: a project-wide individual patient data re-analysis on 1483 intervention participants.
This planned MiSpEx-Network reanalysis was designed to derive a dose-response relationship under consideration of further effect modifiers in exercises on low back pain. One thousand four hundred eighty three intervention participants with low back pain (mean age, 40.9 years [SD 14 years]) performed stabilisation exercises (3 weeks supervised, 9 weeks self-administered). Patients reported pain intensity, disability, and disability days at baseline, 3 weeks, 12 weeks, and 6 months post randomisation. ⋯ The odds ratio for a clinically important effect with higher exercise frequencies decreased at 3 weeks (OR = 0.71 [0.618-0.813] for >2.5*week -1 ) and increased at 12 weeks (1.13 [1.006-1.270], >1.5*week -1 ). Using longer intervention durations, adding a perturbation component to the stabilisation trainings and using higher frequencies (up to a certain point) may lead to an even more beneficial response on exercise in patients with low back pain. Developing strategies to maintain a training frequency of at least 2 times per week may be relevant in stabilisation exercises to treat low back pain.
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Interstitial cystitis/bladder pain syndrome (IC/BPS) is a common and debilitating disease with poor treatment outcomes. Studies from the multidisciplinary approach to the study of chronic pelvic pain research network established that IC/BPS patients with chronic overlapping pain conditions (COPCs) experience poorer quality of life and more severe symptoms, yet the neurobiological correlates of this subtype are largely unknown. We previously showed that ex vivo toll-like receptor 4 (TLR4) cytokine/chemokine release is associated with the presence of COPCs, as well as widespread pain and experimental pain sensitivity women with IC/BPS. ⋯ Controlling for patient age, body mass index, and site of collection, we found that greater ex vivo TLR4-stimulated cytokine/chemokine release was associated with the presence of COPCs ( P < 0.01), extent of widespread pain ( P < 0.05), but not experimental pain sensitivity ( P > 0.05). However, a second component of anti-inflammatory, regulatory, and chemotactic activity was associated with reduced pain sensitivity ( P < 0.01). These results confirm that the IC/BPS + COPCs subtype show higher levels of ex vivo TLR4 cytokine/chemokine release and support a link between immune priming and nociplastic pain in IC/BPS.