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This study determined whether co-injections of L-NAC (500\u00a0\u03bcmol\/kg, IV) or its highly cell-penetrant analogue, L-NAC methyl ester (L-NACme, 500\u00a0\u03bcmol\/kg, IV), prevent acquisition of acute physical dependence induced by twice-daily injections of fentanyl (125\u00a0\u03bcg\/kg, IV), and overcome acquired dependence to these injections in freely-moving male Sprague\u00a0Dawley rats. The injection of the opioid receptor antagonist, naloxone HCl (NLX; 1.5\u00a0mg\/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\u00a0\u03bcg\/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. 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