Pain
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Meta Analysis
Alcohol, coffee consumption, and smoking in relation to migraine: a bidirectional Mendelian randomization study.
We conducted a Mendelian randomization study to assess whether alcohol and coffee consumption and smoking are causally associated with risk of developing migraine. Independent single-nucleotide polymorphisms associated with the potential risk factors at P < 5 × 10-8 in large-scale genome-wide association studies were selected as instrumental variables. Summary-level data for the associations of the selected single-nucleotide polymorphisms with migraine were obtained from the FinnGen consortium comprising 6687 cases and 144,780 noncases and the UK Biobank study comprising 1072 cases and 360,122 noncases. ⋯ In reverse Mendelian randomization analyses, genetic liability to migraine was inversely associated with alcohol consumption but was not associated with coffee consumption or smoking initiation. This study provides genetic evidence in support of a protective role of moderate coffee consumption and a detrimental role of cigarette smoking in the etiology of migraine. The inverse association between alcohol consumption and migraine risk may be attributable to reverse causality.
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Gain-of-function and loss-of-function mutations in Nav1.7 cause chronic pain and pain insensitivity, respectively. The preferential expression of Nav1.7 in the peripheral nervous system and its role in human pain signaling make Nav1.7 a promising target for next-generation pain therapeutics. However, pharmacological agents have not fully recapitulated these pain phenotypes, and because of the lack of subtype-selective molecular modulators, the role of Nav1.7 in the perception of pain remains poorly understood. ⋯ Makatoxin-3 acts on the S3-S4 loop of voltage sensor domain IV (VSD4) of Nav1.7, which causes a hyperpolarizing shift in the steady-state fast inactivation and impairs inactivation kinetics. We also determined the key residues and structure-function relationships for the toxin-channel interactions, which are distinct from those of other well-studied α toxins. This study not only reveals a new mechanism underlying BV-evoked pain but also enriches our knowledge of key structural elements of scorpion toxins that are pivotal for toxin-Nav1.7 interactions, which facilitates the design of novel Nav1.7 selective modulators.
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Chronic pain is associated with mental and physical health difficulties and is prevalent among veterans. Cannabis has been put forth as a treatment for chronic pain, and changes in laws, attitudes, and use patterns have occurred over the past 2 decades. Differences in prevalence of nonmedical cannabis use and cannabis use disorder (CUD) were examined across 2 groups: veterans or nonveterans and those reporting or not reporting recent pain. ⋯ Among veterans, the prevalence of frequent cannabis use was greater among those with pain (PD = 1.92%, 98% CI [0.21-3.63]), and among veterans residing in a state with MCLs, the prevalence of CUD was greater among those reporting recent pain (PD = 3.88%, 98% CI [0.36-7.39]). Findings failed to support the hypothesis that cannabis use improves mental or physical health for veterans with pain. Providers treating veterans with pain in MCL states should monitor such patients closely for CUD.
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Discrimination negatively influences health and well-being in the general population, but its impact on people with pain is unclear. This study assessed discrimination, health, and well-being in people with and without pain. Data were from 5871 participants from the English Longitudinal Study of Ageing. ⋯ People with pain are more likely to report discrimination than those without pain, and this experience is associated with increased depression and loneliness. Discrimination was predictive of incident pain in pain-free adults. These findings highlight the need to tackle discrimination to improve well-being in those with pain and to potentially reduce the risk of pain onset.
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Afferents from the C2 spinal nerve (SN) and trigeminal nerve (TN) innervate neighboring cranial territories, and their convergence on the upper cervical dorsal horn neurons represents neural substrate of pain referral in primary headache disorders. Unfortunately, little is known about trigeminocervical input to the major spinal nociceptive projection area lamina I. Here, we used ex vivo brainstem-cervical cord preparation for the visually guided whole-cell recording from the upper cervical lamina I neurons. ⋯ Thus, trigeminocervical input in lamina I is processed in both nerve-specific and convergent circuitries. Afferent convergence on to inhibitory interneurons serves as a feedforward mechanism balancing excitatory drive to projection neurons. Disruption of this balance may cause pain in primary headache syndromes.