Enhancement of Opioid Antinociception by Nicotine

Abstract

Nicotine can produce antinociception in preclinical pain models; however, the ability of nicotine to augment the antinociceptive effects of opioid agonists has not been investigated. The present experiments were conducted to determine how nicotine modifies the effects of opioid agonists differing in efficacy. Male squirrel monkeys responded for the delivery of milk under a fixed ratio 10 schedule of reinforcement. During the 30-second timeout period following each milk delivery, the subject's tail was immersed in 35, 50, 52, or 55°C water, and the latency to remove the tail was recorded. Dose-response functions for tailwithdrawal latency and operant performance were determined for fentanyl, oxycodone, buprenorphine, and nalbuphine alone and after treatment with nicotine. Excepting nalbuphine, all opioids produced dose-related disruptions in food-maintained responding and increases in tail-withdrawal latency at each water temperature. Nicotine did not exacerbate the behaviorally disruptive effects of the m-opioids on operant performance but produced a significant mecamylamine-sensitive enhancement of the antinociceptive potency of each opioid. Failure of arecoline to augment the antinociceptive effects of oxycodone and antagonism by mecamylamine suggests this nicotine-induced augmentation of prescription opioid antinociception was nicotinic acetylcholine receptor (nAChR) mediated. This was reflected in leftward shifts in the antinociceptive dose-response curve of each opioid, ranging from 2-to 7-fold increases in the potency of oxycodone across all water temperatures to an approximately 70-fold leftward shift in the antinociceptive dose-response curve of nalbuphine at the lower and intermediate water temperatures. These results suggest that nicotine may enhance m-opioid antinociceptive effects without concomitantly exacerbating their behaviorally disruptive effects. SIGNIFICANCE STATEMENT Prescription opioids remain the most effective painmanagement pharmacotherapeutics but are limited by their adverse effects. The present results indicate that nicotine enhances antinociceptive effects of various opioid agonists in nonhuman primates without increasing their disruptive effects on operant performance. These results suggest that nicotine might function as an opioid adjuvant for pain management by enabling decreased clinically effective analgesic doses of prescription opioids without exacerbating their adverse behavioral effects.

One Is Not Enough: Understanding and Modeling Polysubstance Use

“…Similarly, simultaneous administration of opioids and nicotine enhances opioid-evoked DA release in the NAc and dorsal striatum (Vihavainen et al, 2008). Cross-tolerance to opioid-mediated analgesia has also been shown following pre-exposure to nicotine and cannabis (Schmidt et al, 2001), and chronic nicotine treatment dose-dependently reduces analgesic tolerance to opioids in a nACh receptordependent manner (Haghparast et al, 2008;De Moura et al, 2019). Interestingly, pretreatment with Ca 2+ channel blockers or naloxone prevents this tolerance, suggesting a complex pharmacological interaction between opioids and nicotine (Biala and Weglinska, 2006).…”

“…Co-administration of nicotine, alcohol, or heroin enhances psychostimulant-induced DA release into the NAc (Bunney et al, 2001;Mello et al, 2014;Pattison et al, 2014), though specific combinations do so via divergent mechanisms. For example, administration of cocaine and nicotine simultaneously activates VTA DA neurons and disrupts DA reuptake (Mello et al, 2014;De Moura et al, 2019), resulting in a greater magnitude of DA release into the NAc than that evoked from either drug alone. Notably, some polydrug combinations that include psychostimulants have divergent and opposing effects on the C-BG-T circuit.…”

“…Notably, cross-tolerance to opioid analgesia is mediated via divergent mechanisms for different polydrug combinations. Nicotine and opioid cross-tolerance is mediated by µO and nACh receptors (Haghparast et al, 2008;De Moura et al, 2019) while cannabinoid and opioid cross-tolerance is mediated by µO receptors and cannabinoid 1 (CB 1 ) receptors (Pugh et al, 1994(Pugh et al, , 1996.…”