Changes in nitrergic and tachykininergic pathways in rat proximal colon in response to chronic treatment with otilonium bromide.
BACKGROUND
Otilonium bromide (OB) is used as a spasmolytic drug in the treatment of the functional bowel disorder irritable bowel syndrome. Although its acute effects on colonic relaxation are well-characterized, little is known about the effects of chronic administration of OB on enteric neurons, neuromuscular transmission, and interstitial cells of Cajal (ICC), key regulators of the gut function.


METHODS
Adult Sprague-Dawley rats were treated with OB in drinking water at a dose of 2 mg/kg for 30 days. The colons of OB-treated and age-matched control rats were studied by confocal immunohistochemistry to detect immunoreactivity (IR) in myenteric plexus neurons for nitrergic and tachykininergic markers, and also by microelectrode electrophysiology.


RESULTS
Using immunohistochemistry, chronic OB administration did not change total neuron number, assessed by anti-Hu IR, but resulted in a significant increase in NK1 receptor positive neurons, a decrease in neuronal nitric oxide synthase expressing neurons, and a reduction in volume of substance P in nerve fibers in the myenteric plexus. Chronic OB administration potentiated inhibitory and excitatory junction potentials evoked by repetitive electrical field stimulation. The various types of colonic ICC, detected by Kit IR, were not altered nor were slow waves or smooth muscle membrane potential.


CONCLUSIONS
Chronic treatment with OB caused significant changes in the nitrergic and tachykinergic components of the myenteric plexus and in both inhibitory and excitatory neurotransmission in the rat colon.
Enteric NeuroScience Program, Division of Gastroenterology and Hepatology, Mayo Clinic Rochester, Rochester, MN, USA.
G
G
Cipriani
Enteric NeuroScience Program, Division of Gastroenterology and Hepatology, Mayo Clinic Rochester, Rochester, MN, USA.
S J
SJ
Gibbons
Enteric NeuroScience Program, Division of Gastroenterology and Hepatology, Mayo Clinic Rochester, Rochester, MN, USA.
S A
SA
Saravanaperumal
Enteric NeuroScience Program, Division of Gastroenterology and Hepatology, Mayo Clinic Rochester, Rochester, MN, USA.
J
J
Malysz
Enteric NeuroScience Program, Division of Gastroenterology and Hepatology, Mayo Clinic Rochester, Rochester, MN, USA.
L
L
Sha
Enteric NeuroScience Program, Division of Gastroenterology and Hepatology, Mayo Clinic Rochester, Rochester, MN, USA.
J H
JH
Szurszewski
Enteric NeuroScience Program, Division of Gastroenterology and Hepatology, Mayo Clinic Rochester, Rochester, MN, USA.
D R
DR
Linden
Preclinical Development, Menarini Ricerche SpA, Florence, Italy.
S
S
Evangelista
Dept. Experimental and Clinical Medicine, Histology and Embryology Research Unit, Florence, Italy.
M S
MS
Faussone-Pellegrini
Dept. Experimental and Clinical Medicine, Histology and Embryology Research Unit, Florence, Italy.
M G
MG
Vannucchi
Enteric NeuroScience Program, Division of Gastroenterology and Hepatology, Mayo Clinic Rochester, Rochester, MN, USA.
G
G
Farrugia
D000818:Animals; D003106:Colon / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D009197:Myenteric Plexus / Q000187:drug effects / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism; D000644:Quaternary Ammonium Compounds / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018040:Receptors, Neurokinin-1 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D015320:Tachykinins / Q000378:metabolism*
D000644:Quaternary Ammonium Compounds; D018040:Receptors, Neurokinin-1; D015320:Tachykinins; C013934:octylonium; D009569:Nitric Oxide; D052248:Nitric Oxide Synthase Type I; C496322:Nos1 protein, rat
antispasmodic; confocal microscopy; enteric nervous system; excitability; interstitial cells of Cajal; junction potential; myenteric plexus; nerve-evoked activity; slow wave