The ventilatory depressant actions but not the antinociceptive effects of morphine are blunted in rats receiving intravenous infusion of L-cysteine ethyl ester - 15/11/22
, Paulina M. Getsy a, Rita M. Ryan a, Yee-Hsee Hsieh e, James M. Seckler f, Stephen J. Lewis a, g, h, ⁎ Abstract |
This study demonstrates that intravenous infusion of the cell-penetrant thiol ester, L-cysteine ethyl ester (L-CYSee), to adult male Sprague-Dawley rats elicited (a) minor alterations in frequency of breathing, expiratory time, tidal volume, minute ventilation, or expiratory drive but pronounced changes in inspiratory time, end-inspiratory and expiratory pauses, peak inspiratory and expiratory flows, EF50, relaxation time, apneic pause, inspiratory drive and non-eupneic breathing index, (b) minimal changes in arterial blood-gas (ABG) chemistry (pH, pCO2, pO2, SO2) and Alveolar-arterial (A-a) gradient (index of alveolar gas exchange), and (c) minimal changes in antinociception (tail-flick latency). Subsequent injection of morphine (10 mg/kg, IV) elicited markedly smaller effects on the above parameters, ABG chemistry, and A-a gradient in rats receiving L-CYSee, whereas morphine antinociception was not impaired. Infusions of L-cysteine or L-serine ethyl ester (oxygen rather than sulfur moiety), did not affect morphine actions on ABG chemistry or A-a gradient. L-CYSee (250 μmol/kg, IV) injection elicited dramatic changes in ventilatory parameters given 15 min after injection of morphine in rats receiving L-CYSee. Our findings suggest that (a) L-CYSee acts in neurons that drive ventilation, (b) L-CYSee reversal of the adverse actions of morphine on ventilation, ABG chemistry and A-a gradient may be via modulation of intracellular signaling pathways activated by morphine rather than by direct antagonism of opioid receptors since morphine antinociception was not diminished by L-CYSee, and (c) the thiol moiety of L-CYSee is vital to efficacy, (d) intracellular conversion of L-CYSee to an S-nitrosylated form may be part of its mechanism of action.
Le texte complet de cet article est disponible en PDF.Graphical Abstract |
Top Panel: Morphine antinociception - morphine blocks pain via inhibiting Ca2+ entry into neurons processing nociceptive signals. L-cysteine ethyl ester (L-CYSee) enters the cell but is not able to interfere with steps 1–3, namely, Step 1: morphine binds to and activates the µ-opioid receptor (µ-OR). Step 2: The βγ subunits release, bind to, and inhibit Ca2+-channels, thereby blocking signal transduction. Step 3: β-arrestin (β-arr) then binds to the µ-OR triggering endocytosis, and the µ-OR is recycled to the cell surface.
Bottom Panel: Formation of SNO-L-CYSee prevents the signaling events driving morphine depression of breathing. Step 1: NO synthase (NOS) converts L-CYSee to S-nitroso-L-CYSee (SNO-L-CYSee), which binds to the βγ subunits of the µ-OR upon morphine binding. Step 2: The entry of Ca2+ is an essential component of the signaling processes that drive breathing. The binding of SNO-L-CYSee prevents the βγ subunits from inhibiting Ca2+ entry thereby maintaining normal signal transduction processes and preventing morphine suppression of breathing. Step 3: β-arr still binds to the complex and triggers endocytosis, but the presence of SNO-L-CYSee prevents recycling to the membrane, reducing available µ-OR at the cell surface.
Top Panel: Morphine antinociception - morphine blocks pain via inhibiting Ca2+ entry into neurons processing nociceptive signals. L-cysteine ethyl ester (L-CYSee) enters the cell but is not able to interfere with steps 1–3, namely, Step 1: morphine binds to and activates the µ-opioid receptor (µ-OR). Step 2: The βγ subunits release, bind to, and inhibit Ca2+-channels, thereby blocking signal transduction. Step 3: β-arrestin (β-arr) then binds to the µ-OR triggering endocytosis, and the µ-OR is recycled to the cell surface.Bottom Panel: Formation of SNO-L-CYSee prevents the signaling events driving morphine depression of breathing. Step 1: NO synthase (NOS) converts L-CYSee to S-nitroso-L-CYSee (SNO-L-CYSee), which binds to the βγ subunits of the µ-OR upon morphine binding. Step 2: The entry of Ca2+ is an essential component of the signaling processes that drive breathing. The binding of SNO-L-CYSee prevents the βγ subunits from inhibiting Ca2+ entry thereby maintaining normal signal transduction processes and preventing morphine suppression of breathing. Step 3: β-arr still binds to the complex and triggers endocytosis, but the presence of SNO-L-CYSee prevents recycling to the membrane, reducing available µ-OR at the cell surface.ga1Le texte complet de cet article est disponible en PDF.
Keywords : L-thiol ester infusion, Morphine, Ventilatory depression, Arterial blood-gas chemistry, Analgesia, Sprague-Dawley rats
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Vol 156
Article 113939- décembre 2022 Retour au numéro
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