Enhanced Sensitivity of ?3?4 Nicotinic Receptors in Enteric Neurons after Long-Term Morphine: Implication for Opioid-Induced Constipation.

ABSTRACT: 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 ?3 ? ?2 > ?4 > ?5 > ?4 > ?3 > ?6. Nicotine-induced currents were obtained in neurons from ?7, ?2, ?5, and ?6 knockout mice. The currents were, however, inhibited by mecamylamine (10 ?M) and the ?3?4 blocker ?-conotoxin AuIB (3 ?M), suggesting that nicotine-induced currents were mediated by the ?3?4 subtype of nAChRs on enteric neurons. Conversely, NS3861, a partial agonist at ?3?4 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 ?3?4 subtype of nAChR reverses chronic, but not acute, morphine-induced constipation.

SUBMITTER: Gade AR 

PROVIDER: S-EPMC4885510 | biostudies-other | 2016 Jun

REPOSITORIES: biostudies-other