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Migraine constitutes a global health burden, and its pathophysiology is not well-understood; research evaluating cerebral perfusion and altered blood flow between brain areas using non-invasive imaging techniques, such as arterial spin labeling, have been scarce. This study aimed to assess cerebral blood flow (CBF) and its connectivity of migraine.
Learn More >Primary headache disorders are common and burdensome conditions. They are associated to several comorbidities, such as cardiovascular or psychiatric ones, which, in turn, contribute to the global burden of headache. The aim of this study is to provide a comprehensive description of the pooled prevalence of comorbidities of primary headache disorders using a meta-analytical approach based on studies published between 2000 and 2020.
Learn More >To examine associations between chronic pain conditions, pain level, and subclinical/clinical anxiety in community-dwelling older adults.
Learn More >Although virtual reality VR is shown to have short-term analgesic effects in acute pain settings, its long-term efficacy with chronic pain conditions has not been established. This scoping review aims to provide a summary of VR approaches explored in chronic primary and secondary pain conditions as defined by the International Association for the Study of Pain.
Learn More >Voltage-gated sodium (Na) channels control excitable cell functions. While structural investigations have revealed conformation details of different functional states, the mechanisms of both activation and slow inactivation remain unclear. Here, we identify residue T140 in the S4-S5 linker of the bacterial voltage-gated sodium channel NaChBac as critical for channel activation and drug effects on inactivation. Mutations at T140 either attenuate activation or render the channel nonfunctional. Propofol, a clinical anesthetic known to inhibit NaChBac by promoting slow inactivation, binds to a pocket between the S4-S5 linker and S6 helix in a conformation-dependent manner. Using F-NMR to quantify site-specific binding by saturation transfer differences (STDs), we found strong STDs in inactivated, but not activated, NaChBac. Molecular dynamics simulations show a highly dynamic pocket in the activated conformation, limiting STD buildup. In contrast, drug binding to this pocket promotes and stabilizes the inactivated states. Our results provide direct experimental evidence showing distinctly different associations between the S4-S5 linker and S6 helix in activated and inactivated states. Specifically, an exchange occurs between interaction partners T140 and N234 of the same subunit in activation, and T140 and N225 of the domain-swapped subunit in slow inactivation. The drug action on slow inactivation of prokaryotic Na channels seems to have a mechanism similar to the recently proposed "door-wedge" action of the isoleucine-phenylalanine-methionine (IFM) motif on the fast inactivation of eukaryotic Na channels. Elucidating this gating mechanism points to a possible direction for conformation-dependent drug development.
Learn More >This was a multicenter retrospective analysis comparing intravenous push (IVP) analgesia versus patient-controlled analgesia (PCA) in patients admitted for sickle cell pain crisis. The primary objective was to compare the analgesic management, measured in total daily morphine milligram equivalents (MME). Secondary objectives included length of hospitalization, 30-day hospital readmissions and pain scores. Of the 98 patients identified between August 2017 and August 2018, 68 patients were included in this study. There were 51% ( = 35) in the IVP group and 49% ( = 33) in the PCA group. The majority of patients were on 90 or more daily MME prior to admission. The average total daily MME was significantly higher in patients on PCA compared to IVP on the first three days of hospitalization (289 vs 146, < 0.01). Length of hospitalization was not different between patients on IVP and PCA (7.14 vs. 6.39 days, = 0.53). There was no difference in 30-day readmissions, average pain scores on days 1-3 of hospitalization and adverse side effects between the groups. This study showed patients on IVP had significantly lower total daily MME requirements compared to PCA within the first three calendar days of admission.
Learn More >This observational study aimed to assess the difference in disability, burden, and sensitization between migraine patients with low-frequency headache attack (1-8 headache days/month), high-frequency headache attack (9-14 headache days/months), and patients with chronic migraine (>14 headache days/months).
Learn More >A remarkable molecular and functional heterogeneity of the primary sensory neurons and dorsal horn interneurons transmits pain- and or itch-relevant information, but the molecular signature of the projection neurons that convey the messages to the brain is unclear. Here, using retro-TRAP (translating ribosome affinity purification) and RNA sequencing, we reveal extensive molecular diversity of spino- and trigeminoparabrachial projection neurons. Among the many genes identified, we highlight distinct subsets of -, -, -, and -expressing projection neurons. By combining in situ hybridization of retrogradely labeled neurons with Fos-based assays, we also demonstrate significant functional heterogeneity, including both convergence and segregation of pain- and itch-provoking inputs into molecularly diverse subsets of NK1R- and non-NK1R-expressing projection neurons.
Learn More >In a recent issue of Nature, Hoeffel et al. describe a novel pathway of sterile tissue repair utilizing a mouse model of sunburn. This wound healing pathway is coordinated by sensory neuron-derived TAFA4 that induces IL-10 production from Tim4 dermal macrophages to prevent sustained inflammation and the emergence of tissue fibrosis.
Learn More >Opioid drugs are widely used analgesics that activate the G protein-coupled µ-opioid receptor, whose endogenous neuropeptide agonists, endorphins and enkephalins, are potent pain relievers. The therapeutic utility of opioid drugs is hindered by development of tolerance to the analgesic effects, requiring dose escalation for persistent pain control and leading to overdose and fatal respiratory distress. The prevailing hypothesis is that the intended analgesic effects of opioid drugs are mediated by µ-opioid receptor signaling to G protein, while the side-effects of respiratory depression and analgesic tolerance are caused by engagement of the receptor with the arrestin-3 protein. Consequently, opioid drug development has focused exclusively on identifying agonists devoid of arrestin-3 engagement. Here, we challenge the prevailing hypothesis with a panel of six clinically relevant opioid drugs and mice of three distinct genotypes with varying abilities to promote morphine-mediated arrestin-3 engagement. With this genetic and pharmacological approach, we demonstrate that arrestin-3 recruitment does not impact respiratory depression, and effective arrestin-3 engagement reduces, rather than exacerbates, the development of analgesic tolerance. These studies suggest that future development of safer opioids should focus on identifying opioid ligands that recruit both G protein and arrestin-3, thereby mimicking the signaling profile of most endogenous µ-opioid receptor agonists.
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