Simvastatin prevents morphine antinociceptive tolerance and withdrawal symptoms through antioxidative effect and nitric oxide pathway in mice

Houshmand, Gholamreza; Pourasghar, Mehdi; Shiran, Mohammad-Reza; Firozjae, Atefeh Arab; Goudarzi, Mehdi; Manouchehr, Fatemeh; Shirzad, Shizer; Assadpour, Sara; Nikbakht, Jafar; Ghorbanzadeh, Behnam

doi:10.1016/j.bbr.2020.113104

Cited by 8 publications

(1 citation statement)

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“…Frontiers in Pharmacology frontiersin.org Noda and Nabeshima, 2004;Glass, 2011;Fluyau et al, 2020), muscarinic receptors (Marshall and Buccafusco, 1987;Holland et al, 1993), corticotropin-releasing factor (CRF) receptor (CRF1) (García-Carmona et al, 2015), tachykinin receptors (Michaud and Couture, 2003), voltage-gated Ca 2+ -channels (Tokuyama et al, 1995;Dogrul et al, 2002;Esmaeili-Mahani et al, 2008;Alboghobeish et al, 2019), adenylyl cyclase superactivation and opioid receptor phosphorylation (Avido-Reiss et al, 1996;Avido-Reiss et al, 1997;Wang et al, 1999;Eckhardt et al, 2000), oxidative stress (Xu et al, 2006;Mori et al, 2007;Abdel-Zaher et al, 2013;Mansouri et al, 2020;Ward et al, 2020;Houshmand et al, 2021), and the nitric oxide-cGMP signaling cascade (Adams et al, 1993;Cappendijk et al, 1993;Majeed et al, 1994;Vaupel et al, 1995a;Buccafusco et al, 1995;Vaupel et al, 1995b;Herman et al, 1995;Leza et al, 1995;London et al, 1995;Dambisya and Lee, 1996;Bhatt and Kumar, 2015;Tsakova et al, 2015;Sackner et al, 2019;Gledhill and Babey, 2021). Since L-CYSee blunted the expression of all NLXprecipitated behavioral (except for sneezing), physical (body weight loss and hypothermia), and cardiorespiratory (hypertension, tachycardia, and incidence of apneas) phenomena, it is tempting to assume that L-CYSee interrupts fun...…”

Section: Prevention Of Dependencementioning

confidence: 99%

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

Bates,

Getsy,

Coffee

et al. 2023

Front. Pharmacol.

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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 mg/kg, IP), elicited pronounced withdrawal phenomena in rats which received a subcutaneous depot of morphine (150 mg/kg) for 36 h and were receiving a continuous infusion of saline (20 μL/h, IV) via osmotic minipumps for the same 36 h period. The withdrawal phenomena included wet-dog shakes, jumping, rearing, fore-paw licking, 360° 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 μmol/kg/h, IV) for 36 h. NLX precipitated a marked withdrawal syndrome in rats that had received subcutaneous depots of morphine (150 mg/kg) for 48 h) and a co-infusion of vehicle. However, the NLX-precipitated withdrawal signs were markedly reduced in morphine (150 mg/kg for 48 h)-treated rats that began receiving an infusion of L-CYSee (20.8 μmol/kg/h, IV) at 36 h. In similar studies to those described previously, neither L-cysteine nor L-serine ethyl ester (both at 20.8 μmol/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.

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