RT Journal Article SR Electronic T1 Enhanced Sensitivity of α3β4 Nicotinic Receptors in Enteric Neurons after Long-Term Morphine: Implication for Opioid-Induced Constipation JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP 520 OP 528 DO 10.1124/jpet.116.233304 VO 357 IS 3 A1 Aravind R. Gade A1 Minho Kang A1 Fayez Khan A1 John R. Grider A1 M. Imad Damaj A1 William L. Dewey A1 Hamid I. Akbarali YR 2016 UL http://jpet.aspetjournals.org/content/357/3/520.abstract AB Opioid-induced constipation is a major side effect that persists with long-term opioid use. Previous studies demonstrated that nicotine-induced contractions are enhanced after long-term morphine exposure in guinea pig ileum. In the present study, we examined whether the increased sensitivity to nicotine could be observed in single enteric neurons after long-term morphine exposure, determined the subunits in mouse enteric neurons, and examined the effect of nicotine in reversing opioid-induced constipation. Nicotine (0.03–1 mM) dose-dependently induced inward currents from a holding potential of −60 mV in isolated single enteric neurons from the mouse ileum. The amplitude of the currents, but not the potency to nicotine, was significantly increased in neurons receiving long-term (16–24 h) but not short-term (10 min) exposure to morphine. Quantitative mRNA analysis showed that nicotinic acetylcholine receptor (nAChR) subunit expression in the mouse ileum was α3 ≥ β2 > β4 > α5 > α4 > β3 > α6. Nicotine-induced currents were obtained in neurons from α7, β2, α5, and α6 knockout mice. The currents were, however, inhibited by mecamylamine (10 μM) and the α3β4 blocker α-conotoxin AuIB (3 μM), suggesting that nicotine-induced currents were mediated by the α3β4 subtype of nAChRs on enteric neurons. Conversely, NS3861, a partial agonist at α3β4 nAChR, enhanced fecal pellet expulsion in a dose-dependent manner in mice that received long-term, but not short-term, morphine treatment. Overall, our findings suggest that the efficacy of nAChR agonists on enteric neurons is enhanced after long-term morphine exposure, and activation of the α3β4 subtype of nAChR reverses chronic, but not acute, morphine-induced constipation.