Co-injections of L-NAC methyl ester reduce the loss of antinociception and prevent the occurrence of hyperalgesia elicited by injections of fentanyl in male rats.

The development of hyperalgesia (i.e., enhanced physical pain and/or psychological distress) during chronic fentanyl use plays a vital role in the continued and accelerated use of this potent synthetic opioid. Numerous biochemical changes in the brain, such as changes in redox status, are thought to contribute to the development of hyperalgesia to fentanyl and other opioids. This study addresses whether the clinically used antioxidant N-acetyl-L-cysteine (L-NAC) and its readily cell-penetrant analogue, L-NAC methyl ester (L-NACme) would affect the progressive loss of antinociception and appearance of hyperalgesia in adult male Sprague Dawley rats. We monitored changes in tail-flick latencies following twice daily co-injections over 5 days (8 AM, 8 PM) of fentanyl (125 μg/kg, IV) + vehicle or L-NAC (500 μmol/kg, IV) or L-NACme (500 μmol/kg, IV) in the rats. The first co-injections of fentanyl + vehicle elicited a long-lasting antinociception, whereas a robust hyperalgesia appeared with co-injections 5 and was even more dramatic following co-injections 6-10. The co-injections of fentanyl + L-NAC partially prevented the loss of antinociception and occurrence of hyperalgesia, and co-injections of fentanyl and L-NACme markedly reduced the loss of antinociception and prevented the appearance of hyperalgesia. This study provides evidence that L-NAC and L-NACme beneficially affect the alterations in pain processing that occurs with sub-chronic administration of fentanyl. The higher efficacy of L-NACme is likely to be due to its greater cell penetrability in brain regions and interaction with intracellular signaling cascades, which may include redox-dependent processes, that mediate fentanyl-induced antinociception and hyperalgesia.