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Piezo1 and Piezo2 belong to a family of mechanically-activated ion channels implicated in a wide range of physiological processes. Mechanical stimulation triggers Piezo channels to open, but their characteristic fast inactivation process results in rapid closure. Several disease-causing mutations in Piezo1 alter the rate of inactivation, highlighting the importance of inactivation to the normal function of this channel. However, despite the structural identification of two physical constrictions within the closed pore, the mechanism of inactivation remains unknown. Here we identify a functionally conserved inactivation gate in the pore-lining inner helix of mouse Piezo1 and Piezo2 that is distinct from the two constrictions. We show that this gate controls the majority of Piezo1 inactivation via a hydrophobic mechanism and that one of the physical constrictions acts as a secondary gate. Our results suggest that, unlike other rapidly inactivating ion channels, a hydrophobic barrier gives rise to fast inactivation in Piezo channels.
Learn More >Early detection and rapid intervention can prevent death from opioid overdose. At high doses, opioids (particularly fentanyl) can cause rapid cessation of breathing (apnea), hypoxemic/hypercarbic respiratory failure, and death, the physiologic sequence by which people commonly succumb from unintentional opioid overdose. We present algorithms that run on smartphones and unobtrusively detect opioid overdose events and their precursors. Our proof-of- concept contactless system converts the phone into a short-range active sonar using frequency shifts to identify respiratory depression, apnea, and gross motor movements associated with acute opioid toxicity. We develop algorithms and perform testing in two environments: (i) an approved supervised injection facility (SIF), where people self-inject illicit opioids, and (ii) the operating room (OR), where we simulate rapid, opioid-induced overdose events using routine induction of general anesthesia. In the SIF ( = 209), our system identified postinjection, opioid-induced central apnea with 96% sensitivity and 98% specificity and identified respiratory depression with 87% sensitivity and 89% specificity. These two key events commonly precede fatal opioid overdose. In the OR, our algorithm identified 19 of 20 simulated overdose events. Given the reliable reversibility of acute opioid toxicity, smartphone-enabled overdose detection coupled with the ability to alert naloxone-equipped friends and family or emergency medical services (EMS) could hold potential as a low-barrier, harm reduction intervention.
Learn More >Although altered neural networks have been demonstrated in recent MEG (magnetoencephalography) research in migraine patients during resting state, it is unknown whether this alteration can be detected in task-related networks. The present study aimed to investigate the abnormalities of the frequency-specific somatosensory-related network in migraine patients by using MEG.
Learn More >A prospective observational study with translation and psychometric analyses of a questionnaire.
Learn More >Osteoarthritis (OA) is a common joint disease in aging societies, which is accompanied by chronic inflammation and degeneration of the joint structure. Inflammation of the infrapatellar fat pad (IFP) and synovial membrane (IFP surface) plays essential roles in persistent pain development in patients with OA. To identify the point during the inflammatory process critical for persistent pain development, we performed a time course histological analysis in a rat arthritis model.
Learn More >Functional tests are widely used to measure performance in patients with chronic musculoskeletal pain. Our objective was to determine the Minimal Clinically Important Differences (MCID) for the 6-min walk test (6MWT), the Steep Ramp Test (SRT), the 1-min stair climbing test (1MSCT), the sit-to-stand test (STS), the Jamar dynamometer test (JAM) and the lumbar Progressive Isoinertial Lifting Evaluation (PILE) in chronic musculoskeletal pain patients.
Learn More >Prescription opioids are involved in 40% of all deaths from opioid overdose in the United States and are commonly the first opioids encountered by individuals with opioid use disorder. It is unclear whether the pharmaceutical industry marketing of opioids to physicians is associated with mortality from overdoses.
Learn More >OBJECTIVEMotor cortex stimulation (MCS) is a neurosurgical technique used to treat patients with refractory neuropathic pain syndromes. MCS activates the periaqueductal gray (PAG) matter, which is one of the major centers of the descending pain inhibitory system. However, the neurochemical mechanisms in the PAG that underlie the analgesic effect of MCS have not yet been described. The main goal of this study was to investigate the neurochemical mechanisms involved in the analgesic effect induced by MCS in neuropathic pain. Specifically, we investigated the release of γ-aminobutyric acid (GABA), glycine, and glutamate in the PAG and performed pharmacological antagonism experiments to validate of our findings.METHODSMale Wistar rats with surgically induced chronic constriction of the sciatic nerve, along with sham-operated rats and naive rats, were implanted with both unilateral transdural electrodes in the motor cortex and a microdialysis guide cannula in the PAG and subjected to MCS. The MCS was delivered in single 15-minute sessions. Neurotransmitter release was evaluated in the PAG before, during, and after MCS. Quantification of the neurotransmitters GABA, glycine, and glutamate was performed using a high-performance liquid chromatography system. The mechanical nociceptive threshold was evaluated initially, on the 14th day following the surgery, and during the MCS. In another group of neuropathic rats, once the analgesic effect after MCS was confirmed by the mechanical nociceptive test, rats were microinjected with saline or a glycine antagonist (strychnine), a GABA antagonist (bicuculline), or a combination of glycine and GABA antagonists (strychnine+bicuculline) and reevaluated for the mechanical nociceptive threshold during MCS.RESULTSMCS reversed the hyperalgesia induced by peripheral neuropathy in the rats with chronic sciatic nerve constriction and induced a significant increase in the glycine and GABA levels in the PAG in comparison with the naive and sham-treated rats. The glutamate levels remained stable under all conditions. The antagonism of glycine, GABA, and the combination of glycine and GABA reversed the MCS-induced analgesia.CONCLUSIONSThese results suggest that the neurotransmitters glycine and GABA released in the PAG may be involved in the analgesia induced by cortical stimulation in animals with neuropathic pain. Further investigation of the mechanisms involved in MCS-induced analgesia may contribute to clinical improvements for the treatment of persistent neuropathic pain syndromes.
Learn More >Peripheral diabetic neuropathy can be painful and its symptoms include hyperalgesia, allodynia and spontaneous pain. Hydrogen sulfide (HS) is involved in diabetes-induced hyperalgesia and allodynia. However, the molecular target through which HS induces hyperalgesia in diabetic animals is unclear. The aim of this study was to determine the possible involvement of transient receptor potential (TRP) channels in HS-induced hyperalgesia in diabetic rats.
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