Behavioral economics of polysubstance use: The role of orexin-1 receptors in nicotine-induced augmentation of synthetic opioid consumption

Nicotine and opioid use disorders are highly comorbid in clinical populations. Ongoing nicotine administration facilitates opioid consumption in both rodents and humans. Moreover, preclinical studies support that former exposure to nicotine solely during adolescence augments opioid consumption in adulthood similarly to acute nicotine administration. This suggests that developmental nicotine exposure persistently alters the neural substrates underlying motivation in a manner that resembles the acute pharmacological actions of nicotine. The orexin system mediates motivation to consume opioids in large part through signaling at orexin-1 receptors (ORX1Rs). Both developmental nicotine exposure and acute nicotine administration profoundly alter functioning of the orexin system which may mediate the reinforcing enhancing properties of nicotine. Here, we used behavioral economic procedures to generate demand curves for consumption of the synthetic, short-acting, μ-opioid receptor agonist remifentanil (RMF) in adulthood following prior adolescent nicotine exposure (ANE) and again following reintroduction of acute nicotine administration (ANA). We found that ANE was sufficient to augment multiple indices of the motivational value of RMF in adulthood and these effects were further exacerbated by ANA given during RMF self-administration sessions. Additionally, we demonstrate that systemic antagonism of ORX1Rs with SB-334867 is more efficacious in limiting motivation for RMF in nicotine-exposed rats relative to controls and this differential efficacy was even greater in ANA conditions relative to former ANE. These findings support that nicotine-induced facilitation of orexin signaling may mechanistically contribute to augmented opioid consumption offering critical insight for treatment options for a population that is particularly vulnerable to developing opioid use disorder.