Dissociation of Increased 5‐hydroxyindoleacetic Acid Levels and Physical Dependence: The Effects of Naloxone

Abstract

1. A slow release emulsion of naloxone (naloxone SR) was administered subcutaneously to rats in an attempt to induce physical dependence of the morphine type. 2. Naltrexone (2.5 mg/kg), injected i.p., failed to elicit an abstinence syndrome in rats treated with 75, 100 or 150 mg/kg naloxone SR for 24, 48, or 72 h. 3. Naloxone SR had no effect on the whole brain levels of noradrenaline, dopamine, homovanillic acid or serotonin. 4. Naloxone SR caused an apparent dose-related increase in the brain levels of 5-hydroxyindoleacetic acid. 5. These results show that while naloxone does not induce physical dependence of the morphine type, it may, like morphine, increase the brain serotonin turnover rate. 6. It is proposed that the increase in brain serotonin turnover rate may not be causally related to physical dependence on morphine-like drugs but may be a property of drugs containing the basic opiate molecular structure.

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

“…The first set of major observations of this study was that co-infusion of the L-thiol ester, L-CYSee, markedly reduced the expression of multiple withdrawal signs (behavioral, cardiorespiratory, body weight loss, and hypothermia) elicited by the injection of the opioid receptor antagonist, NLX, in male Sprague Dawley rats treated for 36 h with slow-release morphine emulsion. The behavioral withdrawal signs indicative of the rats having become physically dependent on morphine, such as jumping, wet-dog shakes, rearing, fore-paw licking, circling, writhing, and sneezing (rapid expulsions of air), as well as decreases in body weight and body temperature, were consistent with previous reports published using this same slow-release morphine model ( Lee and Fennessy, 1970 ; Laska and Fennessy, 1976 ; Laska and Fennessy, 1977 ; Laska and Fennessy, 1978 ; Lewis et al, 1988b ), and with a wide variety of other administration protocols used to induce morphine dependence ( Hutchinson et al, 2007 ; Lopez-Gimenez and Milligan, 2010 ; Morgan and Christie, 2011 ; Nielsen and Kreek, 2012 ). The increases in MAP and heart rate elicited by NLX are new findings in our morphine-dependence model, but are in full agreement with evidence that NLX-precipitated withdrawal is associated with hypertension and tachycardia in experimental animals ( Buccafusco, 1983 ; Buccafusco, 1990 ; Buccafusco et al, 1984 ; Marshall and Buccafusco, 1985 ; Dixon and Chang, 1988 ; Chang and Dixon, 1990 ; Delle et al, 1990 ; Baraban et al, 1993 ) and humans ( Newlin et al, 1992 ; Purssell et al, 1995 ; Walsh et al, 2003 ; Levin et al, 2019 ; Balshaw et al, 2021 ; Isoardi et al, 2022 ; Lee et al, 2022 ).…”

“…The jugular vein catheter was connected to a primed ALZET osmotic minipump (Model 2002; ALZA Corporation, CA, United States) positioned at the back of the neck to allow continuous infusion of the vehicle (20 μL/h, IV), L-cysteine (20.8 μmol/kg/h, IV), L-CYSee (20.8 μmol/kg/h, IV), or L-SERee (20.8, μmol/kg/h, IV), as described previously ( Jarrott et al, 1987 ; Lewis et al, 1988a ; Jarrott et al, 1988 ; Lewis et al, 1989 ). Physical dependence was induced by a slow-release subcutaneous depot of morphine emulsion (150 mg/kg, SC) injected at the left side of the neck, as described in detail by Fennessy and colleagues ( Lee and Fennessy, 1970 ; Laska and Fennessy, 1976 ; Laska and Fennessy, 1977 ; Laska and Fennessy, 1978 ; Lewis et al, 1988b ). In brief, morphine base was precipitated from a solution of (+)-morphine sulfate by titrating to pH 9 with 1 mol/L NaOH.…”

“…(Jarrott et al, 1987;Lewis et al, 1988a;Jarrott et al, 1988;Lewis et al, 1989). Physical dependence was induced by a slow-release subcutaneous depot of morphine emulsion (150 mg/kg, SC) injected at the left side of the neck, as described in detail by Fennessy and colleagues (Lee and Fennessy, 1970;Laska and Fennessy, 1976;Laska and Fennessy, 1977;Laska and Fennessy, 1978;Lewis et al, 1988b). In brief, morphine base was precipitated from a solution of (+)-morphine sulfate by titrating to pH 9 with 1 mol/L NaOH.…”