Nitrosyl factors play a vital role in the ventilatory depressant effects of fentanyl in unanesthetized rats.
Nitrosyl factors play a vital role in the ventilatory depressant effects of fentanyl in unanesthetized rats.
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DOI：
10.1016/j.biopha.2021.112571
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发表时间：
2022-03
期刊：
影响因子：
--
通讯作者：
Lewis SJ
中科院分区：
文献类型：
--
作者：
Seckler JM;Grossfield A;May WJ;Getsy PM;Lewis SJ
There is an urgent need to understand the intracellular mechanisms by which synthetic opioids, such as fentanyl, depress breathing. We used L-NAME (NG-nitro-L-arginine methyl ester), a nitric oxide synthase (NOS) inhibitor, to provide evidence for a role of nitric oxide (NO) and nitrosyl factors, including S-nitrosothiols, in fentanyl-induced suppression of breathing in rats. We measured breathing parameters using unrestrained plethysmography to record the changes produced by bolus administration of fentanyl (25 μg/kg, IV) in male Sprague Dawley rats that were pretreated with vehicle (saline), L-NAME (50 μmol/kg, IV) or the inactive D-isomer, D-NAME (50 μmol/kg, IV), 15 min previously. L-NAME produced a series of ventilatory changes that included (i) sustained elevations in breathing frequency, due to the reductions in the durations of inspiration and expiration, (ii) sustained elevations in minute ventilation, accompanied by minimal changes in tidal volume, and (iii) increases in inspiratory drive and expiratory drive, and peak inspiratory flow and peak expiratory flow. Subsequent administration of fentanyl in rats pretreated with vehicle produced negative effects on breathing, including decreases in frequency, tidal volume and therefore minute ventilation. Fentanyl elicited markedly different responses in rats that were pretreated with L-NAME, and conclusively, the negative effects of fentanyl were augmented by the NOS inhibitor. D-NAME did not alter ventilatory parameters or modulate the effects of fentanyl on breathing. Our study fully characterized the effects of L-NAME on ventilation in rats and is the first to suggest a potential role of nitrosyl factors in the ventilatory responses to fentanyl. Our data shows that nitrosyl factors reduce the expression of fentanyl-induced changes in ventilation. Panel A: Fentanyl-activated μ-ORs recruit histidine triad nucleotide-binding protein 1 (HINT1) while simultaneously activating neuronal NOS (nNOS). HINT1 then recruits nNOS to the μ-OR-HINT1 complex. nNOS produces small molecule Snitrosothiols and S-nitrosylated proteins which serve to protect against fentanyl-induced respiratory depression. Panel B: Fentanyl-activated μ-ORs recruit HINT1 but nNOS is inhibited by L-NAME and nNOS cannot produce small molecule S-nitrosothiols and S-nitrosylated proteins. Blockade of nNOS has a number of effects including preventing the formation of the μ-OR-NMDA (N-methyl-D-aspartate) receptor super complex, which is a possible mechanism for the potentiation of fentanyl-induced respiratory depression in the absence of NOS activity.
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