Targeting α1- and α2-adrenergic receptors as a countermeasure for fentanyl-induced locomotor and ventilatory depression

Jakob D. Shaykin; Emily D. Denehy; Jocelyn R. Martin; Cassie M. Chandler; Dan Luo; Chase E. Taylor; Michael D. Sunshine; Jill R. Turner; Warren J. Alilain; Thomas E. Prisinzano; Michael T. Bardo

doi:10.1016/j.etap.2024.104527

Targeting α₁- and α₂-adrenergic receptors as a countermeasure for fentanyl-induced locomotor and ventilatory depression

Jakob D. Shaykin, Emily D. Denehy, Jocelyn R. Martin, Cassie M. Chandler, Dan Luo, Chase E. Taylor, Michael D. Sunshine, Jill R. Turner, Warren J. Alilain, Thomas E. Prisinzano, Michael T. Bardo

Research output: Contribution to journal › Article › peer-review

Abstract

This study assessed the ability of α₁ and α₂-adrenergic drugs to decrease fentanyl-induced locomotor and ventilatory depression. Rats were given saline or fentanyl, followed by: (1) naltrexone, (2) naloxone, (3) nalmefene, (4) α₁ agonist phenylephrine, (5) α₁ antagonist prazosin, (6) α_1D antagonist BMY-7378, (7) α₂ agonist clonidine, (8) α₂ antagonist yohimbine or (9) vehicle. All µ-opioid antagonists dose-dependently reversed fentanyl-induced locomotor and ventilatory depression. While the α₁ drugs did not alter the effects of fentanyl, clonidine dose-dependently decreased locomotion and respiration with and without fentanyl. Conversely, yohimbine given at a low dose (0.3–1 mg/kg) stimulated ventilation when given alone and higher doses (>1 mg/kg) partially reversed (∼50 %) fentanyl-induced ventilatory depression, but not locomotor depression. High doses of yohimbine in combination with a suboptimal dose of naltrexone reversed fentanyl-induced ventilatory depression, suggestive of additivity. Yohimbine may serve as an effective adjunctive countermeasure agent combined with naltrexone to rescue fentanyl-induced ventilatory depression.

Original language	English
Article number	104527
Journal	Environmental Toxicology and Pharmacology
Volume	110
DOIs	https://doi.org/10.1016/j.etap.2024.104527
State	Published - Sep 2024

Bibliographical note

Publisher Copyright:
© 2024 Elsevier B.V.

Funding

This work was supported by NIH grants U01 DA051377 and T32 DA035200, an internal grant from NRPA/SUPRA from the University of Kentucky, and the KY-WV Louis Stokes Alliance for Minority Participation. This work was supported by NIH grant U01 DA051377, an internal grant from NRPA/SUPRA from the University of Kentucky, and the KY-WV Louis Stokes Alliance for Minority Participation.

Funders	Funder number
University of Kentucky
SUPRA
NRPA
National Institutes of Health (NIH)	U01 DA051377, T32 DA035200

Keywords

Fentanyl
clonidine
locomotion
ventilation
yohimbine
α-adrenergic

ASJC Scopus subject areas

Toxicology
Pharmacology
Health, Toxicology and Mutagenesis

Access to Document

10.1016/j.etap.2024.104527

Cite this

Shaykin, J. D., Denehy, E. D., Martin, J. R., Chandler, C. M., Luo, D., Taylor, C. E., Sunshine, M. D., Turner, J. R., Alilain, W. J., Prisinzano, T. E., & Bardo, M. T. (2024). Targeting α₁- and α₂-adrenergic receptors as a countermeasure for fentanyl-induced locomotor and ventilatory depression. Environmental Toxicology and Pharmacology, 110, Article 104527. https://doi.org/10.1016/j.etap.2024.104527

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abstract = "This study assessed the ability of α1 and α2-adrenergic drugs to decrease fentanyl-induced locomotor and ventilatory depression. Rats were given saline or fentanyl, followed by: (1) naltrexone, (2) naloxone, (3) nalmefene, (4) α1 agonist phenylephrine, (5) α1 antagonist prazosin, (6) α1D antagonist BMY-7378, (7) α2 agonist clonidine, (8) α2 antagonist yohimbine or (9) vehicle. All µ-opioid antagonists dose-dependently reversed fentanyl-induced locomotor and ventilatory depression. While the α1 drugs did not alter the effects of fentanyl, clonidine dose-dependently decreased locomotion and respiration with and without fentanyl. Conversely, yohimbine given at a low dose (0.3–1 mg/kg) stimulated ventilation when given alone and higher doses (>1 mg/kg) partially reversed (∼50 %) fentanyl-induced ventilatory depression, but not locomotor depression. High doses of yohimbine in combination with a suboptimal dose of naltrexone reversed fentanyl-induced ventilatory depression, suggestive of additivity. Yohimbine may serve as an effective adjunctive countermeasure agent combined with naltrexone to rescue fentanyl-induced ventilatory depression.",

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Shaykin, JD, Denehy, ED, Martin, JR, Chandler, CM, Luo, D, Taylor, CE, Sunshine, MD, Turner, JR , Alilain, WJ , Prisinzano, TE & Bardo, MT 2024, 'Targeting α₁- and α₂-adrenergic receptors as a countermeasure for fentanyl-induced locomotor and ventilatory depression', Environmental Toxicology and Pharmacology, vol. 110, 104527. https://doi.org/10.1016/j.etap.2024.104527

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T1 - Targeting α1- and α2-adrenergic receptors as a countermeasure for fentanyl-induced locomotor and ventilatory depression

AU - Shaykin, Jakob D.

AU - Denehy, Emily D.

AU - Martin, Jocelyn R.

AU - Chandler, Cassie M.

AU - Luo, Dan

AU - Taylor, Chase E.

AU - Sunshine, Michael D.

AU - Turner, Jill R.

AU - Alilain, Warren J.

AU - Prisinzano, Thomas E.

AU - Bardo, Michael T.

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N2 - This study assessed the ability of α1 and α2-adrenergic drugs to decrease fentanyl-induced locomotor and ventilatory depression. Rats were given saline or fentanyl, followed by: (1) naltrexone, (2) naloxone, (3) nalmefene, (4) α1 agonist phenylephrine, (5) α1 antagonist prazosin, (6) α1D antagonist BMY-7378, (7) α2 agonist clonidine, (8) α2 antagonist yohimbine or (9) vehicle. All µ-opioid antagonists dose-dependently reversed fentanyl-induced locomotor and ventilatory depression. While the α1 drugs did not alter the effects of fentanyl, clonidine dose-dependently decreased locomotion and respiration with and without fentanyl. Conversely, yohimbine given at a low dose (0.3–1 mg/kg) stimulated ventilation when given alone and higher doses (>1 mg/kg) partially reversed (∼50 %) fentanyl-induced ventilatory depression, but not locomotor depression. High doses of yohimbine in combination with a suboptimal dose of naltrexone reversed fentanyl-induced ventilatory depression, suggestive of additivity. Yohimbine may serve as an effective adjunctive countermeasure agent combined with naltrexone to rescue fentanyl-induced ventilatory depression.

AB - This study assessed the ability of α1 and α2-adrenergic drugs to decrease fentanyl-induced locomotor and ventilatory depression. Rats were given saline or fentanyl, followed by: (1) naltrexone, (2) naloxone, (3) nalmefene, (4) α1 agonist phenylephrine, (5) α1 antagonist prazosin, (6) α1D antagonist BMY-7378, (7) α2 agonist clonidine, (8) α2 antagonist yohimbine or (9) vehicle. All µ-opioid antagonists dose-dependently reversed fentanyl-induced locomotor and ventilatory depression. While the α1 drugs did not alter the effects of fentanyl, clonidine dose-dependently decreased locomotion and respiration with and without fentanyl. Conversely, yohimbine given at a low dose (0.3–1 mg/kg) stimulated ventilation when given alone and higher doses (>1 mg/kg) partially reversed (∼50 %) fentanyl-induced ventilatory depression, but not locomotor depression. High doses of yohimbine in combination with a suboptimal dose of naltrexone reversed fentanyl-induced ventilatory depression, suggestive of additivity. Yohimbine may serve as an effective adjunctive countermeasure agent combined with naltrexone to rescue fentanyl-induced ventilatory depression.

KW - Fentanyl

KW - clonidine

KW - locomotion

KW - ventilation

KW - yohimbine

KW - α-adrenergic

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