Lipophilic analogues of D-cysteine prevent and reverse physical dependence to fentanyl in male rats
We examined whether co-injections of the cell-permeant D-cysteine analogues, D-cysteine ethyl ester (D-CYSee) and D-cysteine ethyl amide (D-CYSea), prevent acquisition of physical dependence induced by twice-daily injections of fentanyl, and reverse acquired dependence to these injections in freely-...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2024-04-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2023.1336440/full |
| _version_ | 1797221695183912960 |
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| author | James N. Bates Paulina M. Getsy Gregory A. Coffee Santhosh M. Baby Peter M. MacFarlane Yee-Hsee Hsieh Zackery T. Knauss Jason A. Bubier Devin Mueller Stephen J. Lewis Stephen J. Lewis Stephen J. Lewis |
| author_facet | James N. Bates Paulina M. Getsy Gregory A. Coffee Santhosh M. Baby Peter M. MacFarlane Yee-Hsee Hsieh Zackery T. Knauss Jason A. Bubier Devin Mueller Stephen J. Lewis Stephen J. Lewis Stephen J. Lewis |
| author_sort | James N. Bates |
| collection | DOAJ |
| description | We examined whether co-injections of the cell-permeant D-cysteine analogues, D-cysteine ethyl ester (D-CYSee) and D-cysteine ethyl amide (D-CYSea), prevent acquisition of physical dependence induced by twice-daily injections of fentanyl, and reverse acquired dependence to these injections in freely-moving male Sprague Dawley rats. Injection of the opioid receptor antagonist, naloxone HCl (NLX, 1.5 mg/kg, IV), elicited a series of withdrawal phenomena that included cardiorespiratory and behavioral responses, and falls in body weight and body temperature, in rats that received 5 or 10 injections of fentanyl (125 μg/kg, IV), and the same number of vehicle co-injections. Regarding the development of physical dependence, the NLX-precipitated withdrawal phenomena were markedly reduced in fentanyl-injected rats that had received co-injections of D-CYSee (250 μmol/kg, IV) or D-CYSea (100 μmol/kg, IV), but not D-cysteine (250 μmol/kg, IV). Regarding reversal of established dependence to fentanyl, the NLX-precipitated withdrawal phenomena in rats that had received 10 injections of fentanyl (125 μg/kg, IV) was markedly reduced in rats that received co-injections of D-CYSee (250 μmol/kg, IV) or D-CYSea (100 μmol/kg, IV), but not D-cysteine (250 μmol/kg, IV), starting with injection 6 of fentanyl. This study provides evidence that co-injections of D-CYSee and D-CYSea prevent the acquisition of physical dependence, and reverse acquired dependence to fentanyl in male rats. The lack of effect of D-cysteine suggests that the enhanced cell-penetrability of D-CYSee and D-CYSea into cells, particularly within the brain, is key to their ability to interact with intracellular signaling events involved in acquisition to physical dependence to fentanyl. |
| first_indexed | 2024-04-24T13:09:31Z |
| format | Article |
| id | doaj.art-5ab96a619e0f445aae20d91926abf672 |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-04-24T13:09:31Z |
| publishDate | 2024-04-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-5ab96a619e0f445aae20d91926abf6722024-04-05T04:56:00ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122024-04-011410.3389/fphar.2023.13364401336440Lipophilic analogues of D-cysteine prevent and reverse physical dependence to fentanyl in male ratsJames N. Bates0Paulina M. Getsy1Gregory A. Coffee2Santhosh M. Baby3Peter M. MacFarlane4Yee-Hsee Hsieh5Zackery T. Knauss6Jason A. Bubier7Devin Mueller8Stephen J. Lewis9Stephen J. Lewis10Stephen J. Lewis11Department of Anesthesiology, University of Iowa Hospitals and Clinics, Iowa City, IA, United StatesDepartment of Pediatrics, Case Western Reserve University, Cleveland, OH, United StatesDepartment of Pediatrics, Case Western Reserve University, Cleveland, OH, United StatesSection of Biology, Galleon Pharmaceuticals, Inc., Horsham, PA, United StatesDepartment of Pediatrics, Case Western Reserve University, Cleveland, OH, United StatesDivision of Pulmonary, Critical Care and Sleep Medicine, Case Western Reserve University, Cleveland, OH, United StatesDepartment of Biological Sciences, Kent State University, Kent, OH, United StatesThe Jackson Laboratory, Bar Harbor, ME, United StatesDepartment of Biological Sciences, Kent State University, Kent, OH, United StatesDepartment of Pediatrics, Case Western Reserve University, Cleveland, OH, United StatesDepartment of Pharmacology, Case Western Reserve University, Cleveland, OH, United StatesFunctional Electrical Stimulation Center, Case Western Reserve University, Cleveland, OH, United StatesWe examined whether co-injections of the cell-permeant D-cysteine analogues, D-cysteine ethyl ester (D-CYSee) and D-cysteine ethyl amide (D-CYSea), prevent acquisition of physical dependence induced by twice-daily injections of fentanyl, and reverse acquired dependence to these injections in freely-moving male Sprague Dawley rats. Injection of the opioid receptor antagonist, naloxone HCl (NLX, 1.5 mg/kg, IV), elicited a series of withdrawal phenomena that included cardiorespiratory and behavioral responses, and falls in body weight and body temperature, in rats that received 5 or 10 injections of fentanyl (125 μg/kg, IV), and the same number of vehicle co-injections. Regarding the development of physical dependence, the NLX-precipitated withdrawal phenomena were markedly reduced in fentanyl-injected rats that had received co-injections of D-CYSee (250 μmol/kg, IV) or D-CYSea (100 μmol/kg, IV), but not D-cysteine (250 μmol/kg, IV). Regarding reversal of established dependence to fentanyl, the NLX-precipitated withdrawal phenomena in rats that had received 10 injections of fentanyl (125 μg/kg, IV) was markedly reduced in rats that received co-injections of D-CYSee (250 μmol/kg, IV) or D-CYSea (100 μmol/kg, IV), but not D-cysteine (250 μmol/kg, IV), starting with injection 6 of fentanyl. This study provides evidence that co-injections of D-CYSee and D-CYSea prevent the acquisition of physical dependence, and reverse acquired dependence to fentanyl in male rats. The lack of effect of D-cysteine suggests that the enhanced cell-penetrability of D-CYSee and D-CYSea into cells, particularly within the brain, is key to their ability to interact with intracellular signaling events involved in acquisition to physical dependence to fentanyl.https://www.frontiersin.org/articles/10.3389/fphar.2023.1336440/fullfentanylphysical dependenceD-cysteine ethyl esterD-cysteine ethyl amidenaloxonewithdrawal phenomena |
| spellingShingle | James N. Bates Paulina M. Getsy Gregory A. Coffee Santhosh M. Baby Peter M. MacFarlane Yee-Hsee Hsieh Zackery T. Knauss Jason A. Bubier Devin Mueller Stephen J. Lewis Stephen J. Lewis Stephen J. Lewis Lipophilic analogues of D-cysteine prevent and reverse physical dependence to fentanyl in male rats Frontiers in Pharmacology fentanyl physical dependence D-cysteine ethyl ester D-cysteine ethyl amide naloxone withdrawal phenomena |
| title | Lipophilic analogues of D-cysteine prevent and reverse physical dependence to fentanyl in male rats |
| title_full | Lipophilic analogues of D-cysteine prevent and reverse physical dependence to fentanyl in male rats |
| title_fullStr | Lipophilic analogues of D-cysteine prevent and reverse physical dependence to fentanyl in male rats |
| title_full_unstemmed | Lipophilic analogues of D-cysteine prevent and reverse physical dependence to fentanyl in male rats |
| title_short | Lipophilic analogues of D-cysteine prevent and reverse physical dependence to fentanyl in male rats |
| title_sort | lipophilic analogues of d cysteine prevent and reverse physical dependence to fentanyl in male rats |
| topic | fentanyl physical dependence D-cysteine ethyl ester D-cysteine ethyl amide naloxone withdrawal phenomena |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2023.1336440/full |
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