Opioid Antagonists from the Orvinol Series as Potential Reversal Agents for Opioid Overdose.

The opioid crisis continues to claim many lives, with a particular issue being the ready availability and use (whether intentional or accidental) of fentanyl and fentanyl analogues. Fentanyl is both potent and longer-acting than naloxone, the standard of care for overdose reversal, making it especially deadly. Consequently, there is interest in opioid reversal agents that are better able to counter its effects.

Long-term antagonism and allosteric regulation of mu opioid receptors by the novel ligand, methocinnamox.

Opioid overdose is a leading cause of death in the United States. The only treatment available currently is the competitive antagonist, naloxone (Narcan ). Although naloxone is very effective and has saved many lives, as a competitive antagonist it has limitations.

Neuromodulatory Control of Early Visual Processing in Macaque.

Visual processing is dynamically controlled by multiple neuromodulatory molecules that modify the responsiveness of neurons and the strength of the connections between them. In particular, modulatory control of processing in the lateral geniculate nucleus of the thalamus, V1, and V2 will alter the outcome of all subsequent processing of visual information, including the extent to and manner in which individual inputs contribute to perception and decision making and are stored in memory. This review addresses five small-molecule neuromodulators-acetylcholine, dopamine, serotonin, noradrenaline, and histamine-considering the structural basis for their action, and the effects of their release, in the early visual pathway of the macaque monkey.

A qualitative exploration of the psychological impacts of living with the uncertainty of persistent flood risk.

Objectives: Flooding is associated with increased psychological morbidity; however, the impact of living with the uncertainty of flood risk has not been explored. The aim of this study was to generate insight into individual experiences of living with persistent flood risk, how it affects psychological well-being, and the forms of support deemed appropriate to mitigate psychological risks.

Study Design: A qualitative study was conducted using semistructured interviews with participants who lived in a persistent flood risk area in Nottinghamshire, UK.

Understanding the general practice of telemonitoring integrated care: a qualitative perspective.

Developed in partnership with GPs, a new telehealth model of care using remote monitoring, known as telemonitoring (TM), was introduced in South Western Sydney (SWS) in 2015, transmitting clinical readings taken at home to telehealth coordinators. This study explored the experiences, beliefs and attitudes of general practice staff to identify barriers to and facilitators of the SWS TM model. Responses were collected from a purposive sample of 10 participants via semistructured interviews (n = 9 interview sessions) and the resulting transcripts were analysed thematically.

A novel G protein-biased agonist at the μ opioid receptor induces substantial receptor desensitisation through G protein-coupled receptor kinase.

Background And Purpose: G protein-biased μ opioid receptor agonists have the potential to induce less receptor desensitisation and tolerance than balanced opioids. Here, we investigated if the cyclic endomorphin analogue Tyr-c[D-Lys-Phe-Tyr-Gly] (Compound 1) is a G protein-biased μ agonist and characterised its ability to induce rapid receptor desensitisation in mammalian neurones.

Experimental Approach: The signalling and trafficking properties of opioids were characterised using bioluminescence resonance energy transfer assays, enzyme-linked immunosorbent assay and phosphosite-specific immunoblotting in human embryonic kidney 293 cells.

Countermeasures for Preventing and Treating Opioid Overdose.

The only medication available currently to prevent and treat opioid overdose (naloxone) was approved by the US Food and Drug Administration (FDA) nearly 50 years ago. Because of its pharmacokinetic and pharmacodynamic properties, naloxone has limited utility under some conditions and would not be effective to counteract mass casualties involving large-scale deployment of weaponized synthetic opioids. To address shortcomings of current medical countermeasures for opioid toxicity, a trans-agency scientific meeting was convened by the US National Institute of Allergy and Infectious Diseases/National Institutes of Health (NIAID/NIH) on August 6 and 7, 2019, to explore emerging alternative approaches for treating opioid overdose in the event of weaponization of synthetic opioids.

Methocinnamox (MCAM) antagonizes the behavioral suppressant effects of morphine without impairing delayed matching-to-sample accuracy in rhesus monkeys.

Rationale: Opioid abuse remains a serious public health problem. The pseudoirreversible mu opioid receptor antagonist methocinnamox (MCAM) might be useful for treating opioid abuse and overdose. Because endogenous opioid systems can modulate cognition and decision-making, it is important to evaluate whether long-term blockade of mu opioid receptors by MCAM adversely impacts complex operant behavior involving memory.

Pharmacological Properties of -Opioid Receptor-Mediated Behaviors: Agonist Efficacy and Receptor Reserve.

δ-Opioid receptor (-receptor) agonists produce antihyperalgesia, antidepressant-like effects, and convulsions in animals. However, the role of agonist efficacy in generating different -receptor-mediated behaviors has not been thoroughly investigated. To this end, efficacy requirements for -receptor-mediated antihyperalgesia, antidepressant-like effects, and convulsions were evaluated by comparing the effects of the partial agonist BU48 and the full agonist SNC80 and changes in the potency of SNC80 after -receptor elimination.

Effects of acute and repeated treatment with methocinnamox, a mu opioid receptor antagonist, on fentanyl self-administration in rhesus monkeys.

Methocinnamox (MCAM), a mu opioid receptor antagonist with a long duration of action, attenuates heroin self-administration in rhesus monkeys, suggesting it could be an effective treatment for opioid use disorder (OUD). This study examined effects of acute and repeated MCAM administration on self-administration of the high-efficacy mu opioid receptor agonist fentanyl and characterized MCAM pharmacokinetics. Four rhesus monkeys self-administered i.

Functional Clusters of Neurons in Layer 6 of Macaque V1.

Layer 6 appears to perform a very important role in the function of macaque primary visual cortex, V1, but not enough is understood about the functional characteristics of neurons in the layer 6 population. It is unclear to what extent the population is homogeneous with respect to their visual properties or if one can identify distinct subpopulations. Here we performed a cluster analysis based on measurements of the responses of single neurons in layer 6 of primary visual cortex in male macaque monkeys () to achromatic grating stimuli that varied in orientation, direction of motion, spatial and temporal frequency, and contrast.

Diverse Spatiotemporal Scales of Cholinergic Signaling in the Neocortex.

ACh is a signaling molecule in the mammalian CNS, with well-documented influence over cognition and behavior. However, the nature of cholinergic signaling in the brain remains controversial, with ongoing debates focused on the spatial and temporal resolution of ACh activity. Generally, opposing views have embraced a dichotomy between transmission as slow and volume-mediated versus fast and synaptic.

Translational implications of the anatomical nonequivalence of functionally equivalent cholinergic circuit motifs.

Biomedical research is at a critical juncture, with an aging population increasingly beset by chronic illness and prominent failures to translate research from "bench to bedside." These challenges emerge on a background of increasing "silo-ing" of experiments (and experimenters)-many investigators produce and consume research conducted in 1, perhaps 2, species-and increasing pressure to reduce or eliminate research on so-called "higher" mammals. Such decisions to restrict species diversity in biomedical research have not been data-driven and increase the risk of translational failure.

Methocinnamox Produces Long-Lasting Antagonism of the Behavioral Effects of -Opioid Receptor Agonists but Not Prolonged Precipitated Withdrawal in Rats.

A novel -opioid receptor antagonist, methocinnamox (MCAM), attenuates some abuse-related and toxic effects of opioids. This study further characterized the pharmacology of MCAM in separate groups of rats using procedures to examine antinociception, gastrointestinal motility, and withdrawal in morphine-dependent rats. Antinociceptive effects of opioid receptor agonists were measured before and after MCAM (1-10 mg/kg) using warm water tail withdrawal and sensitivity to mechanical stimulation in inflamed paws (complete Freund's adjuvant).

Structure and function of dual-source cholinergic modulation in early vision.

Behavioral states such as arousal and attention have profound effects on sensory processing, determining how-even whether-a stimulus is perceived. This state-dependence is believed to arise, at least in part, in response to inputs from subcortical structures that release neuromodulators such as acetylcholine, often nonsynaptically. The mechanisms that underlie the interaction between these nonsynaptic signals and the more point-to-point synaptic cortical circuitry are not well understood.

Reversal and Prevention of the Respiratory-Depressant Effects of Heroin by the Novel -Opioid Receptor Antagonist Methocinnamox in Rhesus Monkeys.

One consequence of the ongoing opioid epidemic is a large number of overdose deaths. Naloxone reverses opioid-induced respiratory depression; however, its short duration of action limits the protection it can provide. Methocinnamox (MCAM) is a novel opioid receptor antagonist with a long duration of action.

Long-Lasting Effects of Methocinnamox on Opioid Self-Administration in Rhesus Monkeys.

Opioid abuse remains a serious public health challenge, despite the availability of medications that are effective in some patients (naltrexone, buprenorphine, and methadone). This study explored the potential of a pseudoirreversible mu-opioid receptor antagonist [methocinnamox (MCAM)] as a treatment for opioid abuse by examining its capacity to attenuate the reinforcing effects of mu-opioid receptor agonists in rhesus monkeys. In one experiment, monkeys responded for heroin ( = 5) or cocaine ( = 4) under a fixed-ratio schedule.

Most calbindin-immunoreactive neurons, but few calretinin-immunoreactive neurons, express the m1 acetylcholine receptor in the middle temporal visual area of the macaque monkey.

Introduction: Release of the neuromodulator acetylcholine into cortical circuits supports cognition, although its precise role and mechanisms of action are not well understood. Little is known about functional differences in cholinergic modulatory effects across cortical model systems, but anatomical evidence suggests that such differences likely exist because, for example, the expression of cholinergic receptors differs profoundly both within and between species.

Methods: In the primary visual cortex (V1) of macaque monkeys, cholinergic receptors are strongly expressed by inhibitory interneurons.

The novel μ-opioid receptor agonist PZM21 depresses respiration and induces tolerance to antinociception.

Background And Purpose: PZM21 is a novel μ-opioid receptor ligand that has been reported to induce minimal arrestin recruitment and be devoid of the respiratory depressant effects characteristic of classical μ receptor ligands such as morphine. We have re-examined the signalling profile of PZM21 and its ability to depress respiration.

Experimental Approach: G protein (G ) activation and arrestin-3 translocation were measured in vitro, using BRET assays, in HEK 293 cells expressing μ receptors.

Is There a Canonical Cortical Circuit for the Cholinergic System? Anatomical Differences Across Common Model Systems.

Acetylcholine (ACh) is believed to act as a neuromodulator in cortical circuits that support cognition, specifically in processes including learning, memory consolidation, vigilance, arousal and attention. The cholinergic modulation of cortical processes is studied in many model systems including rodents, cats and primates. Further, these studies are performed in cortical areas ranging from the primary visual cortex to the prefrontal cortex and using diverse methodologies.

Modulatory compartments in cortex and local regulation of cholinergic tone.

Neuromodulatory signaling is generally considered broad in its impact across cortex. However, variations in the characteristics of cortical circuits may introduce regionally-specific responses to diffuse modulatory signals. Features such as patterns of axonal innervation, tissue tortuosity and molecular diffusion, effectiveness of degradation pathways, subcellular receptor localization, and patterns of receptor expression can lead to local modification of modulatory inputs.

Optogenetic manipulation of neural circuits in awake marmosets.

Optogenetics has revolutionized the study of functional neuronal circuitry (Boyden ES, Zhang F, Bamberg E, Nagel G, Deisseroth K. Nat Neurosci 8: 1263-1268, 2005; Deisseroth K. Nat Methods 8: 26-29, 2011).

Alkylation of Staurosporine to Derive a Kinase Probe for Fluorescence Applications.

The natural product staurosporine is a high-affinity inhibitor of nearly all mammalian protein kinases. The labelling of staurosporine has proven effective as a means of generating protein kinase research tools. Most tools have been generated by acylation of the 4'-methylamine of the sugar moiety of staurosporine.

A multi-site array for combined local electrochemistry and electrophysiology in the non-human primate brain.

Background: Currently, the primary technique employed in circuit-level study of the brain is electrophysiology, recording local field or action potentials (LFPs or APs). However most communication between neurons is chemical and the relationship between electrical activity within neurons and chemical signaling between them is not well understood in vivo, particularly for molecules that signal at least in part by non-synaptic transmission.

New Method: We describe a multi-contact array and accompanying head stage circuit that together enable concurrent electrophysiological and electrochemical recording.