Repeated, High-dose Fentanyl Administration in Rats Reveals Minimal Tolerance to Unconsciousness, Bradycardia, Muscle Rigidity and Respiratory Depression.

Background: Fentanyl is a synthetic opioid that is widely used in anesthesiology, but its illicit use is rapidly increasing. At high doses fentanyl induces unconsciousness and muscle rigidity, the mechanisms of which are poorly understood. Since animal models are needed to study these effects, the aim of this study was to establish a rat model of fentanyl abuse and investigate the effects of repeated high-dose fentanyl injections on loss of righting reflex, heart rate, respiratory depression, muscle, and brain activity.

Methylphenidate Reversal of Dexmedetomidine-Induced Versus Ketamine-Induced Sedation in Rats.

Background: Dexmedetomidine and ketamine have long elimination half-lives in humans and have no clinically approved reversal agents. Methylphenidate enhances dopaminergic and noradrenergic neurotransmission by inhibiting reuptake transporters for these arousal-promoting neurotransmitters. Previous studies in rats demonstrated that intravenous methylphenidate induces emergence from isoflurane and propofol general anesthesia.

Restoring consciousness with pharmacologic therapy: Mechanisms, targets, and future directions.

Severe brain injury impairs consciousness by disrupting a broad spectrum of neurotransmitter systems. Emerging evidence suggests that pharmacologic modulation of specific neurotransmitter systems, such as dopamine, promotes recovery of consciousness. Clinical guidelines now endorse the use of amantadine in individuals with traumatic disorders of consciousness (DoC) based on level 1 evidence, and multiple neurostimulants are used off-label in clinical practice, including methylphenidate, modafinil, bromocriptine, levodopa, and zolpidem.

Dopaminergic psychostimulants cause arousal from isoflurane-induced sedation without reversing memory impairment in rats.

Background: Dopaminergic psychostimulants can restore arousal in anaesthetised animals, and dopaminergic signalling contributes to hippocampal-dependent memory formation. We tested the hypothesis that dopaminergic psychostimulants can antagonise the amnestic effects of isoflurane on visuospatial working memory.

Methods: Sixteen adult Sprague-Dawley rats were trained on a trial-unique nonmatching-to-location (TUNL) task which assessed the ability to identify a novel touchscreen location after a fixed delay.

Electrical stimulation of the ventral tegmental area restores consciousness from sevoflurane-, dexmedetomidine-, and fentanyl-induced unconsciousness in rats.

Background: Dopaminergic neurons in the ventral tegmental area (VTA) are crucially involved in regulating arousal, making them a potential target for reversing general anesthesia. Electrical deep brain stimulation (DBS) of the VTA restores consciousness in animals anesthetized with drugs that primarily enhance GABA receptors. However, it is unknown if VTA DBS restores consciousness in animals anesthetized with drugs that target other receptors.

Time to Wake Up! The Ongoing Search for General Anesthetic Reversal Agents.

How general anesthetics work remains a topic of ongoing study. A parallel field of research has sought to identify methods to reverse general anesthesia. Reversal agents could shorten patients' recovery time and potentially reduce the risk of postoperative complications.

Oestrous cycle affects emergence from anaesthesia with dexmedetomidine, but not propofol, isoflurane, or sevoflurane, in female rats.

Background: Although sex differences in anaesthetic sensitivity have been reported, what underlies these differences is unknown. In rodents, one source of variability in females is the oestrous cycle. Here we test the hypothesis that the oestrous cycle impacts emergence from general anaesthesia.

Post-cardiac arrest Sedation Promotes Electroencephalographic Slow-wave Activity and Improves Survival in a Mouse Model of Cardiac Arrest.

Background: Patients resuscitated from cardiac arrest are routinely sedated during targeted temperature management, while the effects of sedation on cerebral physiology and outcomes after cardiac arrest remain to be determined. The authors hypothesized that sedation would improve survival and neurologic outcomes in mice after cardiac arrest.

Methods: Adult C57BL/6J mice of both sexes were subjected to potassium chloride-induced cardiac arrest and cardiopulmonary resuscitation.

Return of the Righting Reflex Does Not Portend Recovery of Cognitive Function in Anesthetized Rats.

As the number of individuals undergoing general anesthesia rises globally, it becomes increasingly important to understand how consciousness and cognition are restored after anesthesia. In rodents, levels of consciousness are traditionally captured by physiological responses such as the return of righting reflex (RORR). However, tracking the recovery of cognitive function is comparatively difficult.

Stability of extemporaneously prepared preservative-free methylphenidate 5 mg/mL intravenous solution.

Purpose: To advance the implementation of consciousness-promoting therapies in patients with acute disorders of consciousness, the availability of potential therapeutic agents in formulations suitable for administration in hospitalized patients in the presence of complex comorbid conditions is paramount. The purpose of this study is to evaluate the long-term stability of extemporaneously prepared preservative-free methylphenidate hydrochloride (HCl) 5 mg/mL intravenous solution for experimental use.

Methods: A methylphenidate 5 mg/mL solution was prepared under proper aseptic techniques with Methylphenidate Hydrochloride, USP, powder mixed in sterile water for solution.

Sex, drugs, and anaesthesia research.

In this issue of the British Journal of Anaesthesia, Joksimovic and colleagues report significant sex differences in sensitivity to the behavioural and neurophysiological effects of 3β-OH, a novel neurosteroid anesthetic. Female rats were more sensitive to the effects of 3β-OH than male rats, although the mechanims remain unclear. Sex differences have been understudied in anaesthesia research, and this article by Joksimovic and colleagues emphasizes the need to devote more effort to understanding these differences.

Excitation of Putative Glutamatergic Neurons in the Rat Parabrachial Nucleus Region Reduces Delta Power during Dexmedetomidine but not Ketamine Anesthesia.

Background: Parabrachial nucleus excitation reduces cortical delta oscillation (0.5 to 4 Hz) power and recovery time associated with anesthetics that enhance γ-aminobutyric acid type A receptor action. The effects of parabrachial nucleus excitation on anesthetics with other molecular targets, such as dexmedetomidine and ketamine, remain unknown.

D-Amphetamine Rapidly Reverses Dexmedetomidine-Induced Unconsciousness in Rats.

D-amphetamine induces emergence from sevoflurane and propofol anesthesia in rats. Dexmedetomidine is an α-adrenoreceptor agonist that is commonly used for procedural sedation, whereas ketamine is an anesthetic that acts primarily by inhibiting NMDA-type glutamate receptors. These drugs have different molecular mechanisms of action from propofol and volatile anesthetics that enhance inhibitory neurotransmission mediated by GABA receptors.

The Neural Circuits Underlying General Anesthesia and Sleep.

General anesthesia is characterized by loss of consciousness, amnesia, analgesia, and immobility. Important molecular targets of general anesthetics have been identified, but the neural circuits underlying the discrete end points of general anesthesia remain incompletely understood. General anesthesia and natural sleep share the common feature of reversible unconsciousness, and recent developments in neuroscience have enabled elegant studies that investigate the brain nuclei and neural circuits underlying this important end point.

Challenges faced by cancer patients in Uganda: Implications for health systems strengthening in resource limited settings.

Background: Uganda Cancer Institute (UCI), the only comprehensive cancer treatment center in Uganda, registers about 4000 new cancer patients a year. However, many cancer patients in Uganda never receive treatment due to a variety of challenges. We therefore conducted a study to identify and assess the challenges faced by cancer patients in Uganda.

Activation of GABAergic Neurons in the Rostromedial Tegmental Nucleus and Other Brainstem Regions Promotes Sedation and Facilitates Sevoflurane Anesthesia in Mice.

Many general anesthetics potentiate gamma-aminobutyric acid (GABA) A receptors but their neuroanatomic sites of action are less clear. GABAergic neurons in the rostromedial tegmental nucleus (RMTg) send inhibitory projections to multiple arousal-promoting nuclei, but the role of these neurons in modulating consciousness is unknown. In this study, designer receptors exclusively activated by designer drugs (DREADDs) were targeted to RMTg GABAergic neurons of Vgat-ires-Cre mice.

D-Amphetamine Accelerates Recovery of Consciousness and Respiratory Drive After High-Dose Fentanyl in Rats.

In the United States, fentanyl causes approximately 60,000 drug overdose deaths each year. Fentanyl is also frequently administered as an analgesic in the perioperative setting, where respiratory depression remains a common clinical problem. Naloxone is an efficacious opioid antagonist, but it possesses a short half-life and undesirable side effects.

Personalized Connectome Mapping to Guide Targeted Therapy and Promote Recovery of Consciousness in the Intensive Care Unit.

There are currently no therapies proven to promote early recovery of consciousness in patients with severe brain injuries in the intensive care unit (ICU). For patients whose families face time-sensitive, life-or-death decisions, treatments that promote recovery of consciousness are needed to reduce the likelihood of premature withdrawal of life-sustaining therapy, facilitate autonomous self-expression, and increase access to rehabilitative care. Here, we present the Connectome-based Clinical Trial Platform (CCTP), a new paradigm for developing and testing targeted therapies that promote early recovery of consciousness in the ICU.

Manipulating Neural Circuits in Anesthesia Research.

The neural circuits underlying the distinct endpoints that define general anesthesia remain incompletely understood. It is becoming increasingly evident, however, that distinct pathways in the brain that mediate arousal and pain are involved in various endpoints of general anesthesia. To critically evaluate this growing body of literature, familiarity with modern tools and techniques used to study neural circuits is essential.

The rostromedial tegmental nucleus: a key modulator of pain and opioid analgesia.

A recently defined structure, the rostromedial tegmental nucleus (RMTg; aka tail of the ventral tegmental area [VTA]), has been proposed as an inhibitory control center for dopaminergic activity of the VTA. This region is composed of GABAergic cells that send afferent projections to the ventral midbrain and synapse onto dopaminergic cells in the VTA and substantia nigra. These cells exhibit µ-opioid receptor immunoreactivity, and in vivo, ex vivo, and optogenetic/electrophysiological approaches demonstrate that morphine excites dopamine neurons by targeting receptors on GABAergic neurons localized in the RMTg.

Towards a Comprehensive Understanding of Anesthetic Mechanisms of Action: A Decade of Discovery.

Significant progress has been made in the 21st century towards a comprehensive understanding of the mechanisms of action of general anesthetics, coincident with progress in structural biology and molecular, cellular, and systems neuroscience. This review summarizes important new findings that include target identification through structural determination of anesthetic binding sites, details of receptors and ion channels involved in neurotransmission, and the critical roles of neuronal networks in anesthetic effects on memory and consciousness. These recent developments provide a comprehensive basis for conceptualizing pharmacological control of amnesia, unconsciousness, and immobility.