Enhanced Cholinergic Action of Myenteric Neurons During Chemotherapy Induced Diarrhea

Abstract ID 14356 Poster Board 432 Diarrhea is a prevalent side effect of chemotherapeutic treatment that can result in reduction of quality of life, dose limitation, and death. Irinotecan is a widely used chemotherapeutic in the treatment of unresectable colorectal and metastatic triple-negative breast cancer. It produces both an acute cholinergic mediated diarrhea and a late onset diarrhea that has yet to be fully characterized. Treatment for the acute phase of diarrhea produced by irinotecan is treated with the muscarinic receptor antagonist atropine, however, late onset diarrhea is treated with the mu opioid receptor agonist loperamide. In a population of patients, however, diarrhea becomes refractory to treatment with loperamide. In this study we examine the role of cholinergic response in the development of tolerance to loperamide during late onset diarrhea. Previous reports have demonstrated that in a rodent model of irinotecan-induced diarrhea, choline acetyl transferase (ChAT) and vesicular acetylcholine transporter (VAChT) is increased in myenteric neurons. We hypothesize that enteric neurons become hyperexcitable following irinotecan treatment resulting in enhanced cholinergic activation precluding the efficacy of loperamide in the treatment of late onset diarrhea. In this study we measured neuronal excitability and nicotine-induced currents in isolated myenteric neurons from irinotecan-treated mice. Briefly male ICR mice were treated with 75 mg/kg irinotecan administered intra-peritoneally once daily for four consecutive days followed by monitoring and assessment of diarrhea for two additional days. On day 6 of our paradigm myenteric neurons were isolated and electrophysiological experiments were conducted to examine changes in basal properties. Animals treated with irinotecan produced a decrease in body weight over 6 days, increase in fecal water content, and time dependent increase in diarrhea scoring. We measured the electrophysiological properties of isolated myenteric neurons from irinotecan treated animals. There were no observed differences in resting membrane potentials of treated animals(fig D). Treated animals, however, produced a statistically significant increase in action potential amplitude 94.42 ± 3.03 mV (n=14) when compared to their controls 81.75 ± 3.489 mV (n=14) (P<0001 unpaired t-test) (fig A). Additionally, we found a decrease is the amount of current needed to elicit an action potential (Rheobase) in irinotecan treated animals 21.3 ± 3.065 pA as compared to their control 32 ± 4.047 pA (P<0.05 unpaired t-test) (fig B). In Irinotecan treated animals, nicotine inward currents were enhanced in a dose-dependent manner with maximal current at 1mM increased from -91.7 ± 12.21 pA/pF to -57.016 ± 7.426 pF/pA (n=5) (P<0.01 unpaired t-test) (fig C). Support/Funding Information: NIH-T32DA007027-47