An autonomous implantable device for the prevention of death from opioid overdose.

Opioid overdose accounts for nearly 75,000 deaths per year in the United States, now a leading cause of mortality among young people aged 18 to 45 years. At overdose levels, opioid-induced respiratory depression becomes fatal without the administration of naloxone within minutes. Currently, overdose survival relies on bystander intervention, requiring a nearby person to find the overdosed individual and have immediate access to naloxone to administer.

An Autonomous Implantable Device for the Prevention of Death from Opioid Overdose.

Opioid overdose accounts for nearly 75,000 deaths per year in the United States, representing a leading cause of mortality amongst the prime working age population (25-54 years). At overdose levels, opioid-induced respiratory depression becomes fatal without timely administration of the rescue drug naloxone. Currently, overdose survival relies entirely on bystander intervention, requiring a nearby person to discover and identify the overdosed individual, and have immediate access to naloxone to administer.

A survey of practice in the anesthetic management of adolescent idiopathic scoliosis spine fusion by the North American Pediatric Spine Anesthesiologists Collaborative.

Background: Adolescent Idiopathic Scoliosis (AIS) affects 2%-4% of the general pediatric population. While surgical correction remains one of the most common orthopedic procedures performed in pediatrics, limited consensus exists on the perioperative anesthetic management.

Aims: To examine the current state of anesthetic management of typical AIS spine fusions at institutions which have a dedicated pediatric orthopedic spine surgeon.

Opioid sensitivity in treated and untreated obstructive sleep apnoea: a prospective cohort study.

Background: Opioid administration to patients with obstructive sleep apnoea (OSA) is controversial because they are believed to be more sensitive to opioids. However, objective data on opioid effects in OSA are lacking. We tested the hypothesis that subjects with untreated OSA have increased sensitivity to opioids compared with subjects without OSA, or with OSA treated with continuous positive airway pressure (CPAP) or bilevel positive airway pressure (BIPAP).

Closed-Loop Acoustic Stimulation During Sedation with Dexmedetomidine (CLASS-D): Protocol for a Within-Subject, Crossover, Controlled, Interventional Trial with Healthy Volunteers.

Introduction: The relative power of slow-delta oscillations in the electroencephalogram (EEG), termed slow-wave activity (SWA), correlates with level of unconsciousness. Acoustic enhancement of SWA has been reported for sleep states, but it remains unknown if pharmacologically induced SWA can be enhanced using sound. Dexmedetomidine is a sedative whose EEG oscillations resemble those of natural sleep.

The metabotropic glutamate receptor 5 negative allosteric modulator fenobam: pharmacokinetics, side effects, and analgesic effects in healthy human subjects.

Metabotropic glutamate receptor 5 (mGlu5) has been shown to modulate nociception in animals, but no mGlu5 antagonists have been developed commercially as analgesics. The mGlu5 antagonist fenobam [N-(3-chlorophenyl)-N'-(4,5-dihydro-1-methyl-4-oxo-1H-imidazole-2-yl)urea] was originally evaluated for development as a nonbenzodiazepine anxiolytic. Fenobam is analgesic in numerous mouse pain models, acting exclusively through mGlu5 blockade.

Wireless, battery-free optoelectronic systems as subdermal implants for local tissue oximetry.

Monitoring regional tissue oxygenation in animal models and potentially in human subjects can yield insights into the underlying mechanisms of local O-mediated physiological processes and provide diagnostic and therapeutic guidance for relevant disease states. Existing technologies for tissue oxygenation assessments involve some combination of disadvantages in requirements for physical tethers, anesthetics, and special apparatus, often with confounding effects on the natural behaviors of test subjects. This work introduces an entirely wireless and fully implantable platform incorporating (i) microscale optoelectronics for continuous sensing of local hemoglobin dynamics and (ii) advanced designs in continuous, wireless power delivery and data output for tether-free operation.

Opioid Sensitivity in Children with and without Obstructive Sleep Apnea.

Background: Opioids are a mainstay of perioperative analgesia. Opioid use in children with obstructive sleep apnea is challenging because of assumptions for increased opioid sensitivity and assumed risk for opioid-induced respiratory depression compared to children without obstructive sleep apnea. These assumptions have not been rigorously tested.

Enhanced GABAergic actions resulting from the coapplication of the steroid 3α-hydroxy-5α-pregnane-11,20-dione (alfaxalone) with propofol or diazepam.

Many GABAergic drugs are in clinical use as anesthetics, sedatives, or anxiolytics. We have investigated the actions of the combinations of the neuroactive steroid 3α-hydroxy-5α-pregnane-11,20-dione (alfaxalone) with the intravenous anesthetic propofol or the benzodiazepine diazepam. The goal of the study was to determine whether coapplication of alfaxalone reduces the effective doses and concentrations of propofol and diazepam.

Soft, stretchable, fully implantable miniaturized optoelectronic systems for wireless optogenetics.

Optogenetics allows rapid, temporally specific control of neuronal activity by targeted expression and activation of light-sensitive proteins. Implementation typically requires remote light sources and fiber-optic delivery schemes that impose considerable physical constraints on natural behaviors. In this report we bypass these limitations using technologies that combine thin, mechanically soft neural interfaces with fully implantable, stretchable wireless radio power and control systems.

Reproducibility of the heat/capsaicin skin sensitization model in healthy volunteers.

Introduction: Heat/capsaicin skin sensitization is a well-characterized human experimental model to induce hyperalgesia and allodynia. Using this model, gabapentin, among other drugs, was shown to significantly reduce cutaneous hyperalgesia compared to placebo. Since the larger thermal probes used in the original studies to produce heat sensitization are now commercially unavailable, we decided to assess whether previous findings could be replicated with a currently available smaller probe (heated area 9 cm(2) versus 12.

Metabotropic glutamate receptor 5 antagonism with fenobam: examination of analgesic tolerance and side effect profile in mice.

Background: The metabotropic glutamate receptor 5 noncompetitive antagonist fenobam is analgesic in rodents. Future development of fenobam as an analgesic in humans will require a favorable long-term treatment profile and a lack of significant deleterious side effects. This study aimed to determine whether tolerance to fenobam's analgesic effects developed over 14 days and to assess for side effects in mice.

Metabotropic glutamate receptors as targets for analgesia: antagonism, activation, and allosteric modulation.

The metabotropic glutamate receptors (mGluRs) are expressed pre- and post-synaptically throughout the nervous system where they serve as modulators of synaptic transmission and neuronal excitability. Activation of mGluRs can be pro- or anti-nociceptive, depending on their anatomic location and the signaling cascades to which they couple. Antagonists of Group I mGluRs and agonists of Group II and III mGluRs have shown therapeutic promise in animal pain models.

mGlu2 metabotropic glutamate receptors restrain inflammatory pain and mediate the analgesic activity of dual mGlu2/mGlu3 receptor agonists.

Group II metabotropic glutamate receptors (mGluRs) couple to the inhibitory G-protein Gi. The group II mGluRs include two subtypes, mGlu2 and mGlu3, and their pharmacological activation produces analgesic effects in inflammatory and neuropathic pain states. However, the specific contribution of each one of the two subtypes has not been clarified due to the lack of selective orthosteric ligands that can discriminate between mGlu2 and mGlu3 subtypes.

Activation of metabotropic glutamate receptor 5 in the amygdala modulates pain-like behavior.

The central nucleus of the amygdala (CeA) has been identified as a site of nociceptive processing important for sensitization induced by peripheral injury. However, the cellular signaling components underlying this function remain unknown. Here, we identify metabotropic glutamate receptor 5 (mGluR5) as an integral component of nociceptive processing in the CeA.

The metabotropic glutamate receptor subtype 5 antagonist fenobam is analgesic and has improved in vivo selectivity compared with the prototypical antagonist 2-methyl-6-(phenylethynyl)-pyridine.

Metabotropic glutamate receptor subtype 5 (mGlu5) has been demonstrated to play a role in the modulation of numerous nociceptive modalities. When administered via peripheral, intrathecal, or systemic routes, mGlu5 antagonists have analgesic properties in a variety of preclinical pain models. Despite a wealth of data supporting the use of mGlu5 antagonists to treat pain, studies have been limited to preclinical animal models due to a lack of mGlu5 antagonists that are approved for use in humans.

Cutaneous nociception evoked by 15-delta PGJ2 via activation of ion channel TRPA1.

Background: A number of prostaglandins (PGs) sensitize dorsal root ganglion (DRG) neurons and contribute to inflammatory hyperalgesia by signaling through specific G protein-coupled receptors (GPCRs). One mechanism whereby PGs sensitize these neurons is through modulation of "thermoTRPs," a subset of ion channels activated by temperature belonging to the Transient Receptor Potential ion channel superfamily. Acrid, electrophilic chemicals including cinnamaldehyde (CA) and allyl isothiocyanate (AITC), derivatives of cinnamon and mustard oil respectively, activate thermoTRP member TRPA1 via direct modification of channel cysteine residues.