Effects of excitatory and inhibitory neurotransmission on motor patterns of human sigmoid colon in vitro

Background and purpose: To characterize the in vitro motor patterns and the neurotransmitters released by enteric motor neurons (EMNs) in the human sigmoid colon. Experimental approach: Sigmoid circular strips were studied in organ baths. EMNs were stimulated by electrical field stimulation (EFS) and through nicotinic ACh receptors. Key results: Strips developed weak spontaneous rhythmic contractions (3.67±0.49 g, 2.54±0.15 min) unaffected by the neurotoxin tetrodotoxin (TTX; 1 μM). EFS induced strong contractions during (on, 56%) or after electrical stimulus (off, 44%), both abolished by TTX. Nicotine (1–100 μM) inhibited spontaneous contractions. Latency of off‐contractions and nicotine responses were reduced by NG‐nitro‐L‐arginine (1 mM) and blocked after further addition of apamin (1 μM) or the P2Y1 receptor antagonist MRS 2179 (10 μM) and were unaffected by the P2X antagonist NF279 (10 μM) or α‐chymotrypsin (10 U mL−1). Amplitude of on‐ and off‐contractions was reduced by atropine (1 μM) and the selective NK2 receptor antagonist Bz‐Ala‐Ala‐D‐Trp‐Phe‐D‐Pro‐Pro‐Nle‐NH2 (1 μM). MRS 2179 reduced the amplitude of EFS on‐ and off‐contractions without altering direct muscular contractions induced by ACh (1 nM–1 mM) or substance P (1 nM–10 μM). Conclusions and implications: Latency of EFS‐induced off‐contractions and inhibition of spontaneous motility by nicotine are caused by stimulation of inhibitory EMNs coreleasing NO and a purine acting at muscular P2Y1 receptors through apamin‐sensitive K+ channels. EFS‐induced on‐ and off‐contractions are caused by stimulation of excitatory EMNs coreleasing ACh and tachykinins acting on muscular muscarinic and NK2 receptors. Prejunctional P2Y1 receptors might modulate the activity of excitatory EMNs. P2Y1 and NK2 receptors might be therapeutic targets for colonic motor disorders. British Journal of Pharmacology (2008) 155, 1043–1055; doi:10.1038/bjp.2008.332; published online 1 September 2008