Academic Journal
L-NAC and L-NAC methyl ester prevent and overcome physical dependence to fentanyl in male rats
| Title: | L-NAC and L-NAC methyl ester prevent and overcome physical dependence to fentanyl in male rats |
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| Authors: | James N. Bates, Santhosh M. Baby, Paulina M. Getsy, Gregory A. Coffee, Yee-Hsee Hsieh, Zackery T. Knauss, Albert Dahan, Jason A. Bubier, Peter M. MacFarlane, Devin Mueller, Stephen J. Lewis |
| Source: | Scientific Reports, Vol 14, Iss 1, Pp 1-16 (2024) |
| Publisher Information: | Nature Portfolio, 2024. |
| Publication Year: | 2024 |
| Collection: | LCC:Medicine LCC:Science |
| Subject Terms: | Fentanyl, Physical dependence, N-acetyl-L-cysteine, N-acetyl-L-cysteine ethyl ester, Naloxone, Withdrawal phenomena, Medicine, Science |
| More Details: | Abstract 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. |
| Document Type: | article |
| File Description: | electronic resource |
| Language: | English |
| ISSN: | 2045-2322 |
| Relation: | https://doaj.org/toc/2045-2322 |
| DOI: | 10.1038/s41598-024-59551-0 |
| Access URL: | https://doaj.org/article/7cf134f1aa4b40f786d4d28221785b6e |
| Accession Number: | edsdoj.7cf134f1aa4b40f786d4d28221785b6e |
| Database: | Directory of Open Access Journals |
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| ISSN: | 20452322 |
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| DOI: | 10.1038/s41598-024-59551-0 |
| Published in: | Scientific Reports |
| Language: | English |