{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T08:46:00Z","timestamp":1792485960527,"version":"4.5.0"},"reference-count":264,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,12,4]],"date-time":"2023-12-04T00:00:00Z","timestamp":1701648000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>The molecular mechanisms underlying the acquisition of addiction\/dependence on 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 the co-administration of the cell-penetrant L-thiol ester, L-cysteine ethyl ester (L-CYSee), would reduce physical dependence on morphine in male Sprague Dawley rats. Injection of the opioid-receptor antagonist, naloxone HCl (NLX; 1.5\u00a0mg\/kg, IP), elicited pronounced withdrawal phenomena in rats which received a subcutaneous depot of morphine (150\u00a0mg\/kg) for 36\u00a0h and were receiving a continuous infusion of saline (20\u00a0\u03bcL\/h, IV) via osmotic minipumps for the same 36\u00a0h period. The withdrawal phenomena included wet-dog shakes, jumping, rearing, fore-paw licking, 360\u00b0 circling, writhing, apneas, cardiovascular (pressor and tachycardia) responses, hypothermia, and body weight loss. NLX elicited substantially reduced withdrawal syndrome in rats that received an infusion of L-CYSee (20.8\u00a0\u03bcmol\/kg\/h, IV) for 36\u00a0h. NLX precipitated a marked withdrawal syndrome in rats that had received subcutaneous depots of morphine (150\u00a0mg\/kg) for 48\u00a0h) and a co-infusion of vehicle. However, the NLX-precipitated withdrawal signs were markedly reduced in morphine (150\u00a0mg\/kg for 48\u00a0h)-treated rats that began receiving an infusion of L-CYSee (20.8\u00a0\u03bcmol\/kg\/h, IV) at 36\u00a0h. In similar studies to those described previously, neither L-cysteine nor L-serine ethyl ester (both at 20.8\u00a0\u03bcmol\/kg\/h, IV) mimicked the effects of L-CYSee. This study demonstrates that 1) L-CYSee attenuates the development of physical dependence on morphine in male rats and 2) prior administration of L-CYSee reverses morphine dependence, most likely by intracellular actions within the brain. The lack of the 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 analogs may be a novel class of therapeutics that ameliorate the development of physical dependence on opioids in humans.<\/jats:p>","DOI":"10.3389\/fphar.2023.1303207","type":"journal-article","created":{"date-parts":[[2023,12,4]],"date-time":"2023-12-04T10:33:01Z","timestamp":1701685981000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["L-cysteine ethyl ester prevents and reverses acquired physical dependence on morphine in male Sprague Dawley rats"],"prefix":"10.3389","volume":"14","author":[{"given":"James N.","family":"Bates","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paulina M.","family":"Getsy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory A.","family":"Coffee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Santhosh M.","family":"Baby","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter M.","family":"MacFarlane","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yee-Hsee","family":"Hsieh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zackery T.","family":"Knauss","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason A.","family":"Bubier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Devin","family":"Mueller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen J.","family":"Lewis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,12,4]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1016\/j.bbr.2013.02.034","article-title":"Role of oxidative stress and inducible nitric oxide synthase in morphine-induced tolerance and dependence in mice. 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