Enhancement of Opioid Antinociception by Nicotinic Ligands

Abstract

Nicotine has previously been shown to augment the antinociceptive effects of μ-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 nicotinic acetylcholine receptor (nAChR) agonist epibatidine and partial α4β2 nAChR agonist varenicline to selectively augment the antinociceptive effects of the μ-opioid receptor (MOR) full agonist fentanyl, the MOR partial agonist nalbuphine, and the κ-opioid receptor (KOR) agonist U69,593 in male squirrel monkeys. Results indicate that both nAChR ligands selectively increased the antinociceptive effects of nalbuphine and that 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 dihydro-β-erythroidine, consistent with α4β2 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 an 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 may also 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 μ-opioid receptor analgesics without exacerbating their effects on operant performance. The present study demonstrates that the nicotinic acetylcholine receptor (nAChR) agonist epibatidine and partial α4β2 nAChR agonist varenicline can also augment the antinociceptive effects of nalbuphine, as well as those of a κ-opioid receptor 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.

Fig. 1.

Rate-decreasing effects and tail-withdrawal latencies at 50, 52, and 55°C for fentanyl alone (open circles) or in combination with varenicline (top panels, gray circles) or epibatidine (bottom panels, gray circles) (n = 4). Left panel: ordinate, response rate normalized to baseline rate of responding. Right panels: ordinate, tail-withdrawal latency in seconds. Error bars depict ±S.E.M. Sec=seconds.

Fig. 2.

Rate-decreasing effects and tail-withdrawal latencies at 50, 52, and 55°C for nalbuphine alone (open circles) or in combination with varenicline (top panels, gray circles), varenicline + 0.1 mg/kg mecamylamine (top panels, filled circles), epibatidine (bottom panels, gray circles), or epibatidine + 0.1 mg/kg mecamylamine (bottom panels, filled circles) (n = 4). Left panel: ordinate, response rate normalized to baseline rate of responding. Right panels: ordinate, tail-withdrawal latency in seconds. Error bars depict ±S.E.M. Sec=seconds

Fig. 3.

Rate-decreasing effects and tail-withdrawal latencies at 50, 52, and 55°C for nalbuphine alone (open circles) or in combination with varenicline (top panels, gray circles), varenicline + 0.1 mg/kg DHβE (top panels, filled squares), epibatidine (bottom panels, gray circles), or epibatidine + 0.1 mg/kg DHβE (bottom panels, filled squares) (n = 4). Left panel: ordinate, response rate normalized to baseline rate of responding. Right panels: ordinate, tail-withdrawal latency in seconds. Error bars depict ±S.E.M. Sec=seconds.

Fig. 4.

Rate-decreasing effects and tail-withdrawal latencies at 50, 52, and 55°C for U69,593 alone (open circles) or in combination with epibatidine (gray circles) (n = 4). Left panel: ordinate, response rate normalized to baseline rate of responding. Right panels: ordinate, tail-withdrawal latency in seconds. Error bars depict ±S.E.M. Sec=seconds