L-NAC and L-NAC methyl ester prevent and overcome physical dependence to fentanyl in male rats

• Published in: Scientific reports 2024-04, Vol.14 (1), p.9091-16, Article 9091
• Main Authors: Bates, James N., Baby, Santhosh M., Getsy, Paulina M., Coffee, Gregory A., Hsieh, Yee-Hsee, Knauss, Zackery T., Dahan, Albert, Bubier, Jason A., MacFarlane, Peter M., Mueller, Devin, Lewis, Stephen J.
• Format: Article
• Language: English
• Subjects: 631/154; 631/553; 692/308; Acetylcysteine; Acetylcysteine - analogs & derivatives; Animals; Body weight; Body weight loss; Drug abuse; Drug addiction; Drug withdrawal; Fentanyl; Fentanyl - pharmacology; Humanities and Social Sciences; Hypothermia; Injection; Intracellular signalling; Lysine - analogs & derivatives; Male; Morphine Dependence; multidisciplinary; N-acetyl-L-cysteine; N-acetyl-L-cysteine ethyl ester; Naloxone; Naloxone - pharmacology; Narcotic Antagonists - pharmacology; Narcotics; Opioid receptors; Physical dependence; Rats; Rats, Sprague-Dawley; Science; Science (multidisciplinary); Substance Withdrawal Syndrome; Withdrawal phenomena
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-024-59551-0

N-acetyl-L-cysteine (L-NAC) is a proposed therapeutic for opioid use disorder. This study determined whether co-injections of L-NAC (500 μmol/kg, IV) or its highly cell-penetrant analogue, L-NAC methyl ester (L-NACme, 500 μmol/kg, IV), prevent acquisition of acute physical dependence induced by twice-daily injections of fentanyl (125 μg/kg, IV), and overcome acquired dependence to these injections in freely-moving male Sprague Dawley rats. The injection of the opioid receptor antagonist, naloxone HCl (NLX; 1.5 mg/kg, IV), elicited a series of withdrawal phenomena (i.e. behavioral and cardiorespiratory responses, hypothermia and body weight loss) in rats that received 5 or 10 injections of fentanyl and similar numbers of vehicle co-injections. With respect to the development of dependence, the NLX-precipitated withdrawal phenomena were reduced in rats that received had co-injections of L-NAC, and more greatly reduced in rats that received co-injections of L-NACme. In regard to overcoming established dependence, the NLX-precipitated withdrawal phenomena in rats that had received 10 injections of fentanyl (125 μg/kg, IV) were reduced in rats that had received co-injections of L-NAC, and more greatly reduced in rats that received co-injections of L-NACme beginning with injection 6 of fentanyl. This study provides compelling evidence that co-injections of L-NAC and L-NACme prevent the acquisition of physical dependence and overcome acquired dependence to fentanyl in male rats. The higher efficacy of L-NACme is likely due to its greater cell penetrability in brain regions mediating dependence to fentanyl and interaction with intracellular signaling cascades, including redox-dependent processes, responsible for the acquisition of physical dependence to fentanyl.