Breathing Rhythm and Pattern and Their Influence on Emotion

Annual Review of Neuroscience, Год журнала: 2022, Номер 45(1), С. 223 - 247

Опубликована: Март 9, 2022

Breathing is a vital rhythmic motor behavior with surprisingly broad influence on the brain and body. The apparent simplicity of breathing belies complex neural control system, central pattern generator (bCPG), that exhibits diverse operational modes to regulate gas exchange coordinate an array behaviors. In this review, we focus selected advances in our understanding bCPG. At core bCPG preBötzinger (preBötC), which drives inspiratory rhythm via unexpectedly sophisticated emergent mechanism. Synchronization dynamics underlying preBötC rhythmogenesis imbue system robustness lability. These are modulated by inputs from throughout generate rhythmic, patterned activity widely distributed. connectivity emerging literature support link between breathing, emotion, cognition becoming experimentally tractable. bring great potential for elucidating function dysfunction other mammalian circuits.

Язык: Английский

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Critical Assessment of G Protein-Biased Agonism at the μ-Opioid Receptor

Trends in Pharmacological Sciences, Год журнала: 2020, Номер 41(12), С. 947 - 959

Опубликована: Окт. 20, 2020

G protein-biased agonists of the µ-opioid receptor have been hypothesized to be an improved class opioid analgesicsEarly studies in β-arrestin2-knockout mouse that suggested a separation between signaling mediating analgesia versus side effects not reproduced, and 'G protein-biased' mutant MOPr does support original proposal.There is now evidence for protein-dependent signal deleterious effects.The previously observed protein bias many recently developed has confounded by assay amplification. Such ligands may fact unbiased, with low intrinsic efficacy.Current proposal agonism at will provide substantially therapeutic profiles.Low efficacy represents alternative mechanism which novel opioids display wider windows. μ-opioid (MOPr) proposed as analgesics. Recent unable reproduce experiments led this proposal, genetic models do agonist hypothesis. Furthermore, assessment putatively biased several factors, including As such, extent current lead compounds represent mechanistically novel, extremely question, underlying assumption β-arrestin2 mediates effects. Addressing these challenges pressing issue successfully advance drug development improve upon (see Glossary) widely analgesics [1.Siuda E.R. et al.Biased mu-opioid ligands: promising new generation pain therapeutics.Curr. Opin. Pharmacol. 2017; 32: 77-84Crossref PubMed Scopus (99) Google Scholar,2.Smith J.S. signalling: from simple switches allosteric microprocessors.Nat. Rev. Drug Discov. 2018; 17: 243-260Crossref (327) Scholar]. The prototypical such agonist, oliceridine (TRV130), proceeded Phase III clinical trials [3.Viscusi al.APOLLO-1: randomized placebo active-controlled phase study investigating ligand receptor, management moderate-to-severe acute following bunionectomy.J. Pain Res. 2019; 12: 927-943Crossref (72) Scholar], was approved USA use pain. Existing, clinically analgesics, morphine, oxycodone, fentanyl, are relief unmatched other classes. Current array adverse effects, respiratory depression, constipation, euphoria, well inducing tolerance dependence over time. These important limitations all addressed (Box 1). However, recent results brought into question hypothesis underpins action anticipated class, In addition, there both likely analgesics.Box 1The Protein-Biased Agonism HypothesisG maintain eponymous signal, established mediate analgesia, while minimizing recruitment β-arrestin receptor. MOPr/β-arrestin interactions mediate, or positively facilitate, tolerance, physical dependence. Therefore, agonists, dramatically improved, less addictive induce lesser depression constipation (Figure I). initial [10.Raehal K.M. al.Morphine beta-arrestin 2 knockout mice.J. Exp. Ther. 2005; 314: 1195-1201Crossref (413) Scholar,38.Bohn L.M. al.Enhanced morphine mice lacking 2.Science. 1999; 286: 2495-2498Crossref (767) Scholar,40.Bohn al.Mu-opioid desensitization beta-arrestin-2 determines but dependence.Nature. 2000; 408: 720-723Crossref (695) Scholar] repeated later [22.Kliewer A. al.Morphine-induced independent signalling.Br. J. 2020; 177: 2923-2931Crossref (93) Scholar,26.Azevedo Neto partial search safer analgesics.Molecules. 25: E3870Crossref (27) Scholar,42.Koblish M. al.TRV0109101, promote opioid-induced mechanical allodynia chronic administration.J. 362: 254-262Crossref (26) expressing phosphorylation-deficient recruit β-arrestins also [23.Kliewer al.Phosphorylation-deficient G-protein-biased receptors diminish worsen effects.Nat. Commun. 10: 367Crossref (128) substantial accumulated mechanisms analgesia.The profile apparently main text), minimally β-arrestin-recruiting significantly opioids, [76.Conibear A.E. Kelly E. A view receptors?.Mol. 96: 542-549Crossref (54) (but see [51.Gillis al.Low activation can explain effect profiles agonists.Sci. Signal. 13eaaz3140Crossref (109) Scholar,53.Vasudevan L. al.Assessment structure-activity relationships Mu synthetic using stable bio-assay platform.Biochem. 177113910Crossref (25) Scholar]), initially reported rodent potency antinociceptive [6.DeWire S.M. al.A potently analgesic reduced gastrointestinal dysfunction compared morphine.J. 2013; 344: 708-717Crossref (407) Clinical trial candidate mixed, persistent marginally window some measures Scholar,77.Soergel D.G. TRV130 increases reduces on-target morphine: randomized, double-blind, placebo-controlled, crossover healthy volunteers.Pain. 2014; 155: 1829-1835Abstract Full Text PDF (190) Scholar,78.Ayad S. al.Evaluating incidence associated measured frequency average cumulative duration dosing interruption patients treated postoperative pain.Clin. Investig. 40: 755-764Crossref (15) regard abuse-related volunteers rated similarly questionnaire [77.Soergel and, rodents, self-administration of, facilitation intracranial self-stimulation induced similar [79.Altarifi A.A. al.Effects treatment mu (oliceridine) on antinociception, function, abuse liability rodents.J. Psychopharmacol. 31: 730-739Crossref (107) Scholar,80.Zamarripa C.A. al.The G-protein TRV130, produces reinforcing comparable oxycodone rats.Drug Alcohol Depend. 192: 158-162Crossref (51) Additionally, generalized fentanyl drug-discrimination procedure, [69.Schwienteck K.L. al.Effectiveness comparisons unbiased warm water tail-withdrawal discrimination male female rats.Neuropharmacology. 150: 200-209Crossref (21) second compound, PZM21 [48.Hill R. depresses respiration induces antinociception.Br. 175: 2653-2661Crossref Scholar,51.Gillis rewarding conditioned-place preference test [8.Manglik al.Structure-based discovery effects.Nature. 2016; 537: 185-190Crossref (544) found albeit variation experimenters, observation minimal reproduced [81.Kudla al.Functional characterization opioid, PZM21, its behavioural responses morphine.Br. 176: 4434-4445Crossref (17) examination non-human primates showed [82.Ding H. al.Antinociceptive, reinforcing, pruritic signalling-biased primates.Br. Anaesth. 125: 596-604Abstract develops prolonged Scholar].Recently, protein-bias factor family newly correlated antinociception [7.Schmid C.L. al.Bias correlate predict analgesics.Cell. 171: 1165-1175Abstract (260) Most significantly, SR17018 although again shown decreases rate doses Studies hampered poor solubility [46.Grim T.W. signaling-biased reverses preventing withdrawal.Neuropsychopharmacology. 45: 416-425Crossref (34) high, DAMGO-like arrestin [58.Gutman E.S. al.G-protein agonists: 3-hydroxy-N-phenethyl-5-phenylmorphans three-carbon chain substituents C9.RSC Med. Chem. 11: 896-904Crossref analgesia. Recently, target MOPr, coupled (GPCR) signals predominantly through Gαi/o βγ proteins. alters neuronal function well-established mechanisms, postsynaptic inwardly rectifying potassium channels (GIRK), causing hyperpolarization inhibition neurons [4.Williams J.T. al.Enkephalin opens mammalian central neurones.Nature. 1982; 299: 74-77Crossref (186) Presynaptic neurotransmission occurs via voltage-gated calcium (VGCC) [5.Schroeder J.E. al.Activation inhibits transient high- low-threshold Ca2+ currents, spares sustained current.Neuron. 1991; 6: 13-20Abstract (178) negatively regulated system intracellular C-terminal phosphorylation various kinases, binding common most GPCRs. addition negative regulation signaling, transduce protein-independent To date, however, nature putative described it remains unclear how discrete physiological Central benefit Scholar, 7.Schmid 8.Manglik 9.Varadi al.Mitragynine/corynantheidine pseudoindoxyls delta antagonism, beta-arrestin-2.J. 59: 8381-8397Crossref (158) based obtained Opioid-induced major cause overdose death, multiple rather than δ- κ-opioid subtypes (DOPr KOPr) opioid-related nociceptin/orphanin FQ (NOPr) Scholar,11.Matthes H.W. al.Activity delta-opioid partially reduced, whereas activity kappa-receptor maintained mu-receptor.J. Neurosci. 1998; 18: 7285-7295Crossref Scholar,12.Hill al.Fentanyl respiration: comparison heroin 254-266Crossref (43) transit [13.Kieffer B.L. Gaveriaux-Ruff C. Exploring gene knockout.Prog. Neurobiol. 2002; 66: 285-306Crossref (498) Expression abundant throughout network brainstem [14.Montandon G. Slutsky A.S. Solving crisis: cr

Язык: Английский

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Toxicities of opioid analgesics: respiratory depression, histamine release, hemodynamic changes, hypersensitivity, serotonin toxicity

Archives of Toxicology, Год журнала: 2021, Номер 95(8), С. 2627 - 2642

Опубликована: Май 11, 2021

Язык: Английский

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Treatment of overdose in the synthetic opioid era

Pharmacology & Therapeutics, Год журнала: 2021, Номер 233, С. 108019 - 108019

Опубликована: Окт. 11, 2021

Overdose deaths are often viewed as the leading edge of opioid epidemic which has gripped United States over past two decades (Skolnick, 2018a). This emphasis is perhaps unsurprising because overdose both number-one cause death for individuals between 25 and 64 years old (Dezfulian et al., 2021) a significant contributor to decline in average lifespan (Dowell 2017). Exacerbated by COVID 19 pandemic, it was estimated there were 93,400 drug during 12 months ending December 2020, with more than 69,000 (that is, >74%) these fatalities attributed (Ahmad 2021). However, focus on mortality statistics 2021; Shover 2020) tends obscure broader medical impact nonfatal overdose. Analyses multiple databases indicate that each opioid-induced fatality, 6.4 8.4 non-fatal overdoses, exacting burden individual society. Over 7-8 years, been an alarming increase misuse synthetic opioids ("synthetics"), primarily fentanyl related piperidine-based analogs. Within 2-3 structurally unrelated class high potency synthetics, benzimidazoles exemplified etonitazene isotonitazene ("iso"), have also appeared illicit markets (Thompson, 2020; Ujvary al. In 80% fatal overdoses now involve synthetics The unique physicochemical pharmacological properties described this review responsible morbidity associated their well widespread availability. dramatic referred "3rd wave" (Pardo 2019; Volkow Blanco, epidemic. Among consequences resulting from potent need higher doses competitive antagonist, naloxone, reverse development effective reversal agents such those essential component tripartite strategy (Volkow Collins, 2017) reduce biopsychosocial "synthetic era".

Язык: Английский

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Divergent brainstem opioidergic pathways that coordinate breathing with pain and emotions

Neuron, Год журнала: 2021, Номер 110(5), С. 857 - 873.e9

Опубликована: Дек. 17, 2021

Язык: Английский

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Neuronal mechanisms underlying opioid-induced respiratory depression: our current understanding

Journal of Neurophysiology, Год журнала: 2021, Номер 125(5), С. 1899 - 1919

Опубликована: Апрель 7, 2021

Opioid-induced respiratory depression (OIRD) represents the primary cause of death associated with therapeutic and recreational opioid use. Within United States, rate from abuse since early 1990s has grown disproportionally, prompting classification as a nationwide “epidemic.” Since this time, we have begun to unravel many fundamental cellular systems-level mechanisms opioid-related death. However, factors such individual vulnerability, neuromodulatory compensation, redundancy effects across central peripheral nervous systems created barrier concise, integrative view OIRD. review, bring together multiple perspectives in field OIRD create an overarching viewpoint what know, where essential topic research going forward into future.

Язык: Английский

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Understanding and countering opioid‐induced respiratory depression

British Journal of Pharmacology, Год журнала: 2021, Номер 180(7), С. 813 - 828

Опубликована: Июнь 5, 2021

Respiratory depression is the proximal cause of death in opioid overdose, yet mechanisms underlying this potentially fatal outcome are not well understood. The goal review to provide a comprehensive understanding pharmacological opioid‐induced respiratory depression, which could lead improved therapeutic options counter as other detrimental effects opioids on breathing. development tolerance system also discussed, differences degree caused by various agonists. Finally, potential future agents aimed at reversing or avoiding through non‐opioid receptor targets and certain advantages over naloxone. By providing an overview network, will benefit research countering depression. LINKED ARTICLES This article part themed issue Advances Opioid Pharmacology Time Epidemic. To view articles section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v180.7/issuetoc

Язык: Английский

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Neural basis of opioid-induced respiratory depression and its rescue

Proceedings of the National Academy of Sciences, Год журнала: 2021, Номер 118(23)

Опубликована: Май 31, 2021

Significance Opioid-induced respiratory depression (OIRD) is the direct cause of death from opioid overdose, which accounts for current global crisis. Here, we report that neurons expressing μ-opioid receptors in lateral parabrachial nucleus pontine group are necessary and sufficient pathogenesis OIRD. Activating these through endogenous or artificial G protein–coupled receptor signaling pathways rescues OIRD intact mice, suggesting its therapeutic utility patients.

Язык: Английский

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Efferent projections of CGRP/Calca‐expressing parabrachial neurons in mice

The Journal of Comparative Neurology, Год журнала: 2021, Номер 529(11), С. 2911 - 2957

Опубликована: Март 14, 2021

The parabrachial nucleus (PB) is composed of glutamatergic neurons at the midbrain-hindbrain junction. These form many subpopulations, one which expresses Calca, encodes neuropeptide calcitonin gene-related peptide (CGRP). This Calca-expressing subpopulation has been implicated in a variety homeostatic functions, but overall distribution this region remains unclear. Also, while previous studies rats and mice have identified output projections from CGRP-immunoreactive or neurons, we lack comprehensive understanding their efferent projections. We began by identifying with Calca mRNA CGRP immunoreactivity around PB, including populations locus coeruleus motor trigeminal nucleus. PB prominently express mu opioid receptor (Oprm1) are distinct neighboring that Foxp2 Pdyn. Next, used Cre-dependent anterograde tracing synaptophysin-mCherry to map these neurons. heavily target subregions amygdala, bed stria terminalis, basal forebrain, thalamic intralaminar ventral posterior parvicellular nuclei, hindbrain, different patterns depending on injection site location within region. Retrograde axonal revealed previously unreported hindbrain arise rostral-ventral subset CGRP/Calca Finally, show those information provides detailed neuroanatomical framework for interpreting experimental work involving CGRP/Calca-expressing action

Язык: Английский

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GPCR signaling bias: an emerging framework for opioid drug development

The Journal of Biochemistry, Год журнала: 2024, Номер 175(4), С. 367 - 376

Опубликована: Фев. 2, 2024

Abstract Biased signaling, also known as functional selectivity, has emerged an important concept in drug development targeting G-protein-coupled receptors (GPCRs). Drugs that provoke biased signaling are expected to offer opportunity for enhanced therapeutic effectiveness with minimized side effects. Opioid analgesics, whilst exerting potent pain-relieving effects, have become a social problem owing their serious For the of safer pain medications, there been extensive exploration agonists distinct balance G-protein and β-arrestin (βarr) signaling. Recently, several approaches based on protein–protein interactions developed precisely evaluate individual signal pathways, paving way comprehensive analysis signals. In this review, we describe overview bias opioid receptors, especially μ-opioid receptor (MOR), how GPCR field. We discuss future directions rational through integration diverse datasets.

Язык: Английский

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