Abstract

Nicotine previously has been shown to augment the antinociceptive effects of m-opioid agonists in squirrel monkeys without producing a concomitant increase in behavioral disruption. The present studies were conducted to extend these findings by determining the ability of the nAChR agonist epibatidine and partial a4b2 nAChR agonist varenicline to also selectively augment the antinociceptive effects of the MOR full agonist fentanyl, the MOR partial agonist nalbuphine, and the KOR agonist U69,593 in male squirrel monkeys. Results indicate that both nAChR ligands selectively increased the antinociceptive effects of nalbuphine and epibatidine increased the antinociceptive effects of U69,593 without altering effects on operant behavior. However, neither epibatidine nor varenicline enhanced the antinociceptive effects of fentanyl, perhaps due to its high efficacy. The enhancement of nalbuphine's antinociceptive effects by epibatidine, but not varenicline, could be antagonized by either mecamylamine or DHbE, consistent with a4b2 mediation of epibatidine's effects but suggesting the involvement of non-nAChR mechanisms in the effects of varenicline. The present results support previous findings showing that a nAChR agonist can serve as an adjuvant for MOR antinociception and, based on results with U69,593, further indicate that the adjuvant effects of nAChR drugs also may apply to antinociception produced by KOR. Our findings support the further evaluation of nAChR agonists as adjuvants of opioid pharmacotherapy for pain management and point out the need for further investigation into the mechanisms by which they produce opioid-adjuvant effects.

Significance Statement Nicotine has been shown to augment the antinociceptive effects of MOR analgesics without exacerbating their effects on operant performance. The present study demonstrates that the nAChR agonist epibatidine and partial a4b2 nAChR agonist varenicline can also augment the antinociceptive effects of nalbuphine, as well as those of a KOR agonist, without concomitantly exacerbating their behaviorally disruptive effects. These findings support the view that nAChR agonists and partial agonists may have potential as adjuvant therapies for opioid-based analgesics.