AUTHOR=Bates James N. , Getsy Paulina M. , Coffee Gregory A. , Baby Santhosh M. , MacFarlane Peter M. , Hsieh Yee-Hsee , Knauss Zackery T. , Bubier Jason A. , Mueller Devin , Lewis Stephen J. 

TITLE=L-cysteine ethyl ester prevents and reverses acquired physical dependence on morphine in male Sprague Dawley rats

JOURNAL=Frontiers in Pharmacology

VOLUME=Volume 14 - 2023

YEAR=2023

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2023.1303207

DOI=10.3389/fphar.2023.1303207

ISSN=1663-9812

ABSTRACT=The molecular mechanisms underlying the acquisition of addiction/dependence to morphine may result from the ability of the opioid to diminish the transport of L-cysteine into neurons via inhibition of excitatory amino acid transporter 3 (EAA3). The objective of this study was to determine whether co-administration of the cell-penetrant L-thiol ester, L-cysteine ethyl ester (L-CYSee), would reduce physical dependence to morphine in male Sprague-Dawley rats. Injection of the opioid-receptor antagonist, naloxone HCl (NLX; 1.5 mg/kg, IP), elicited pronounced withdrawal phenomena in rats which received a subcutaneous depot of morphine (150 mg/kg) for 36h and which were receiving a continuous infusion of saline (20 L/h, IV) via osmotic minipumps for the same 36h period. The withdrawal phenomena included wet-dog shakes, jumping, rearing, forepaw licking, 360 o circling, writhing, apneas, cardiovascular (pressor and tachycardic) responses, hypothermia and body weight loss. NLX elicited substantially reduced withdrawal syndrome in rats that received an infusion of L-CYSee (20.8 μmol/kg/h, IV) for 36h. NLX precipitated a marked withdrawal syndrome in rats that had received subcutaneous depots of morphine (150 mg/kg) for 48h) and a co-infusion of vehicle. However, the NLX-precipitated withdrawal signs were markedly reduced in morphine (150 mg/kg for 48h)-treated rats that began receiving an infusion of L-CYSee (20.8 mol/kg/h, IV) at 36h. In similar studies to those described above, neither L-cysteine nor L-serine ethyl ester (both at 20.8 mol/kg/h, IV) mimicked the effects of L-CYSee. This study demonstrates that L-CYSee attenuates the development of physical dependence to morphine in male rats and reverses dependence acquired prior to administration of L-CYSee, most likely by intracellular actions within the brain. The lack of effect of L-serine ethyl ester (oxygen atom instead of sulfur atom) strongly implicates thiol biochemistry in the efficacy of L-CYSee. Accordingly, L-CYSee and analogues may be a novel class of therapeutics that ameliorate the development of physical dependence to opioids in humans.