Dynamic Rhythmogenic Network States Drive Differential Opioid Responses in theIn VitroRespiratory Network

Journal of Neuroscience, Journal Year: 2021, Volume and Issue: 41(48), P. 9919 - 9931

Published: Oct. 25, 2021

Death from opioid overdose is typically caused by opioid-induced respiratory depression (OIRD). A particularly dangerous characteristic of OIRD its apparent unpredictability. The consequences opioids can be surprisingly inconsistent, even within the same individual. Despite significant clinical implications, most studies have focused on average dose–r esponses rather than individual variation, and there remains little insight into etiology this preBötzinger complex (preBötC) in ventral medulla an important site for generating rhythm OIRD. Here, using male female C57-Bl6 mice vitro , we demonstrate that preBötC assume different network states depending excitability intrinsic membrane properties neurons. These predict functional preBötC, state, rhythmogenesis either stabilized or suppressed opioids. We hypothesize dynamic nature rhythmogenic properties, required to endow breathing with remarkable flexibility, also plays a key role unpredictability SIGNIFICANCE STATEMENT Opioids cause unpredictable, life-threatening suppression breathing. This makes management difficult while making it challenging define underlying mechanisms find brainstem slices opioid-sensitive subregion brainstem, has optimal configuration cellular results maximally stable rhythm. are dynamic, state each relative predicts how vulnerable effects insights establish framework understanding endogenous exogenous modulation increase decrease risk

Language: Английский

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Coexpressedδ-,μ-, andκ-Opioid Receptors Modulate Voltage-Gated Ca²⁺Channels in Gastric-Projecting Vagal Afferent Neurons

Molecular Pharmacology, Journal Year: 2024, Volume and Issue: 105(3), P. 250 - 259

Published: Jan. 5, 2024

Opioid analgesics are frequently associated with gastrointestinal side effects, including constipation, nausea, dysphagia, and reduced gastric motility. Though it has been shown that stimulation of opioid receptors expressed in enteric motor neurons contributes to opioid-induced remains unclear whether activation gastric-projecting nodose ganglia the reduction motility emptying use. In present study, whole-cell patch-clamp recordings were performed determine mechanism underlying receptor–mediated modulation Ca²⁺ currents acutely isolated vagal afferent neurons. Our results demonstrate Ca_V2.2 channels provide majority (71% ± 16%) Furthermore, we found application oxycodone, U-50488, or deltorphin II on inhibited through a voltage-dependent by coupling Gα_i/o family heterotrimeric G-proteins. Because previous studies have demonstrated expresses low levels δ-opioid receptors, also determined concentration-response relationship assessed deltorphin-mediated current inhibition following exposure receptor antagonist ICI 174,864 (0.3 µM). The peak mean was 47% 24% (EC₅₀ = 302.6 nM), blocked II–mediated (4% 4% versus 37% 20%). Together, our suggest targeting any subtype can modulate circuits.

SIGNIFICANCE STATEMENT

This study neurons, agonists all three classical subtypes (μ, δ, κ) inhibit voltage-gated Gα_i/o. These findings would circuits responsible for regulating reflexes.

Language: Английский

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Dysphagia as a Missing Link Between Post-surgical- and Opioid-Related Pneumonia

Lung, Journal Year: 2024, Volume and Issue: 202(2), P. 179 - 187

Published: March 27, 2024

Language: Английский

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The Immunological and Pharmacokinetic Evaluation of Lipid-PLGA Hybrid Nanoparticle-Based Oxycodone Vaccines

Biomaterials, Journal Year: 2024, Volume and Issue: 313, P. 122758 - 122758

Published: Aug. 18, 2024

Language: Английский

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Theophylline reverses oxycodone's but not fentanyl's respiratory depression in mice while caffeine is ineffective against both opioids

Pharmacology Biochemistry and Behavior, Journal Year: 2023, Volume and Issue: 229, P. 173601 - 173601

Published: July 4, 2023

Language: Английский

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