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Adults with sleep problems are at higher risk for onset of musculoskeletal pain, but the evidence is less clear for children. This prospective cohort study investigated whether children with sleep problems are at higher risk for onset of musculoskeletal pain and explored whether sex is a modifier of this association. In a prospective cohort study of Australian schoolchildren (n = 1239, mean age 9 years), the associations between sleep problems at baseline and new onset of both musculoskeletal pain and persistent musculoskeletal pain (pain lasting > 3 months) 1 year later were investigated using logistic regression. The potential modifying effect of sex was also assessed. One-year incidence proportion for musculoskeletal pain onset is 43% and 7% for persistent musculoskeletal pain. Sleep problems were associated with musculoskeletal pain onset and persistent musculoskeletal pain onset in boys, odds ratio 2.80 (95% CI 1.39, 5.62) and OR 3.70 (1.30, 10.54), respectively, but not girls OR 0.58 (0.28, 1.19) and OR 1.43 (0.41, 4.95), respectively.Conclusions: Rates of musculoskeletal pain are high in children. Boys with sleep problems are at greater risk of onset of musculoskeletal pain, but girls do not appear to have higher risk. Consideration of sleep health may help prevent persistent musculoskeletal pain in children.What is Known:• Sleep problems are associated with the onset of musculoskeletal pain in adults.• It is not clear if the association between sleep problems and the onset of musculoskeletal pain is present also in children and if sex plays a role in this association.What is New:• This is the first large population-based study that has prospectively investigated the relationship between sleep problems and onset of musculoskeletal pain in school-aged children.• Children, especially boys with sleep problems, were at increased risk for the development of persistent musculoskeletal pain.
Learn More >Brain-derived neurotrophic factor (BDNF), a major focus for regenerative therapeutics, has been lauded for its pro-survival characteristics and involvement in both development and recovery of function within the central nervous system (CNS). However, studies of tyrosine receptor kinase B (TrkB), a major receptor for BDNF, indicate that certain effects of the TrkB receptor in response to disease or injury may be maladaptive. More specifically, imbalance among TrkB receptor isoforms appears to contribute to aberrant signaling and hyperpathic pain. A truncated isoform of the receptor, TrkB.T1, lacks the intracellular kinase domain of the full length receptor and is up-regulated in multiple CNS injury models. Such up-regulation is associated with hyperpathic pain, and TrkB.T1 inhibition reduces neuropathic pain in various experimental paradigms. Deletion of TrkB.T1 also limits astrocyte changes in vitro, including proliferation, migration, and activation. Mechanistically, TrkB.T1 is believed to act through release of intracellular calcium in astrocytes, as well as through interactions with neurotrophins, leading to cell cycle activation. Together, these studies support a potential role for astrocytic TrkB.T1 in hyperpathic pain and suggest that targeted strategies directed at this receptor may have therapeutic potential.
Learn More >The analysis of particular (electroencephalographic) EEG frequency bands has revealed new insights relative to the neural dynamics that, when studying the EEG spectrum as a whole, would have remained hidden. This study is aimed at characterizing spectral resting state EEG patterns for assessing possible differences of episodic and chronic migraine during the interictal period. For that purpose, a novel methodology for analyzing specific frequencies of interest was performed.
Learn More >Chronic pain can be the result of an underlying disease or condition, medical treatment, inflammation, or injury. The number of persons experiencing this type of pain is substantial, affecting upwards of 50 million adults in the United States. Pharmacotherapy of most of the severe chronic pain patients includes drugs such as gabapentinoids, re-uptake blockers and opioids. Unfortunately, gabapentinoids are not effective in up to two-thirds of this population and although opioids can be initially effective, their long-term use is associated with multiple side effects. Therefore, there is a great need to develop novel non-opioid alternative therapies to relieve chronic pain. For this purpose, we screened a small library of natural products and their derivatives in the search for pharmacological inhibitors of voltage-gated calcium and sodium channels, which are outstanding molecular targets due to their important roles in nociceptive pathways. We discovered that the acetylated derivative of the ent-kaurane diterpenoid, geopyxin A, 1-O-acetylgeopyxin A, blocks voltage-gated calcium and tetrodotoxin-sensitive voltage-gated sodium channels but not tetrodotoxin-resistant sodium channels in dorsal root ganglion (DRG) neurons. Consistent with inhibition of voltage-gated sodium and calcium channels, 1-O-acetylgeopyxin A reduced reduce action potential firing frequency and increased firing threshold (rheobase) in DRG neurons. Finally, we identified the potential of 1-O-acetylgeopyxin A to reverse mechanical allodynia in a preclinical rat model of HIV-induced sensory neuropathy. Dual targeting of both sodium and calcium channels may permit block of nociceptor excitability and of release of pro-nociceptive transmitters. Future studies will harness the core structure of geopyxins for the generation of antinociceptive drugs.
Learn More >Neuroinflammation plays a vital role in the development and maintenance of neuropathic pain. Recent evidence has proved that bone marrow mesenchymal stem cells (BMSCs) can inhibit neuropathic pain and possess potent immunomodulatory and immunosuppressive properties via secreting a variety of bioactive molecules, such as TNF-α-stimulated gene 6 protein (TSG-6). However, it is unknown whether BMSCs exert their analgesic effect against neuropathic pain by secreting TSG-6. Therefore, the present study aimed to evaluate the analgesic effects of TSG-6 released from BMSCs on neuropathic pain induced by chronic constriction injury (CCI) in rats and explored the possible underlying mechanisms in vitro and in vivo.
Learn More >Headache sufferers in need of professional health care often do not utilize the care available, and factors influencing headache-specific physician consultation are not yet understood. Objectives of this study are (1) to assess self-reported headache-specific physician consultations and (2) to identify headache-related and sociodemographic predictors.
Learn More >Low back pain is a prevalent condition that causes a substantial health burden. Despite intensive and expensive clinical efforts, its prevalence is growing. Nonpharmacologic treatments are effective at improving pain-related outcomes; however, treatment effect sizes are often modest. Physical therapy (PT) and cognitive behavioral therapy (CBT) have the most consistent evidence of effectiveness. Growing evidence also supports mindfulness-based approaches. Discussions with providers and patients highlight the importance of discussing and trying options to find the treatment that works for them and determining what to do when initial treatment is not successful. Herein, we present the protocol for a study that will evaluate evidence-based, protocol-driven treatments using PT, CBT, or mindfulness to examine comparative effectiveness and optimal sequencing for patients with chronic low back pain.
Learn More >This quality improvement project was implemented in order to highlight the association between headache, mTBI and depression on lost productivity and resource utilization.
Learn More >Opioids, such as morphine and fentanyl, are widely used for the treatment of severe pain; however, prolonged treatment with these drugs leads to the development of tolerance and can lead to opioid use disorder. The "Opioid Epidemic" has generated a drive for a deeper understanding of the fundamental signaling mechanisms of opioid receptors. It is generally thought that the three types of opioid receptors (μ, δ, κ) are activated by endogenous peptides derived from three different precursors: Proopiomelanocortin, proenkephalin, and prodynorphin. Posttranslational processing of these precursors generates >20 peptides with opioid receptor activity, leading to a long-standing question of the significance of this repertoire of peptides. Here, we address some aspects of this question using a technical tour de force approach to systematically evaluate ligand binding and signaling properties ([S]GTPγS binding and β-arrestin recruitment) of 22 peptides at each of the three opioid receptors. We show that nearly all tested peptides are able to activate the three opioid receptors, and many of them exhibit agonist-directed receptor signaling (functional selectivity). Our data also challenge the dogma that shorter forms of β-endorphin do not exhibit receptor activity; we show that they exhibit robust signaling in cultured cells and in an acute brain slice preparation. Collectively, this information lays the groundwork for improved understanding of the endogenous opioid system that will help in developing more effective treatments for pain and addiction.
Learn More >A highly potent, selective NaV1.7 inhibitor, DS-1971a has been discovered. Exploration of the left-hand phenyl ring of sulfonamide derivatives (I and II) led to the discovery of novel series of cycloalkane derivatives with high NaV1.7 inhibitory potency in vitro. As the right-hand heteroaromatic ring affected the mechanism-based inhibition liability of CYP3A4, replacement of this moiety resulted in the generation of 4-pyrimidyl derivatives. Additionally, GSH adducts formation, which can cause idiosyncratic drug toxicity, was successfully avoided by this modification. An additional optimization led to the discovery of DS-1971a. In preclinical studies, DS-1971a demonstrated highly potent selective in vitro profile with robust efficacy in vivo. DS-1971a exhibited a favorable toxicological profile, which enabled multiple-dose studies of up to 600 mg bid or 400 mg tid (1200 mg/day) administered for 14 days to healthy human males. DS-1971a is expected to exert potent efficacy in patients with peripheral neuropathic pain, with a favorable safety profile.
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