fedotozine and Abdominal-Pain

Topics: Abdominal Pain; Animals; Benzyl Compounds; Carbolines; Central Nervous System; Colitis, Ulcerative; Colon; Colonic Diseases, Functional; Colonoscopy; Controlled Clinical Trials as Topic; Diarrhea; Digestion; Electromyography; Female; Follow-Up Studies; Gastric Emptying; Gastroenteritis; Gastrointestinal Agents; Gastrointestinal Motility; Humans; Indoles; Intestines; Male; Myenteric Plexus; Neurons; Neurotransmitter Agents; Placebos; Pressure; Propylamines; Receptors, Opioid, kappa; Rectum; Risk Factors; Serotonin Antagonists; Serotonin Receptor Agonists; Sex Factors; Time Factors

Fedotozine, a kappa opioid agonist, reverses digestive ileus caused by acetic acid (AA)-induced visceral pain in rats. The aims of this study were: to map, in conscious rats, central pathways activated by AA using Fos as a marker of neuronal activation; to characterize primary afferent fibres involved in this activation; and to investigate the effect of fedotozine on AA-induced Fos expression. AA (0.6%; 10 mL kg-1) was injected i.p. in conscious rats either untreated; pretreated 14 days before with capsaicin; pretreated 20 min previously with fedotozine; or pretreated 2 h prior to fedotozine with the kappa-antagonist nor-binaltorphimine (nor-BNI). Controls received the vehicle alone. 60 min after injection of AA, rats were processed for Fos immunohistochemistry. Visceral pain was assessed by counting abdominal cramps. AA induced Fos in the thoraco-lumbar spinal cord (laminae I, V, VII and X) and numerous brain structures such as the nucleus tractus solitarius, and paraventricular nucleus (PVN) of the hypothalamus, whereas almost no Fos labelling was observed in controls. Capsaicin pretreatment blocked AA-induced Fos in all structures tested. Fedotozine significantly decreased AA-induced abdominal cramps and Fos immunoreactivity in the spinal cord and PVN, this effect being reversed by nor-BNI pretreatment. AA induces Fos in the spinal cord and numerous brain nucuei, some of which are involved in the control of digestive motility in rats. This effect is mediated through capsaicin-sensitive afferent fibres and prevented by fedotozine most likely through a peripheral action on visceral afferents.

Topics: Abdominal Pain; Acetic Acid; Afferent Pathways; Animals; Benzyl Compounds; Brain; Capsaicin; Gene Expression Regulation; Genes, fos; Injections, Intraperitoneal; Intestinal Obstruction; Male; Naltrexone; Paraventricular Hypothalamic Nucleus; Propylamines; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley; Receptors, Opioid, kappa; Solitary Nucleus; Spinal Cord; Supraoptic Nucleus

The effect of fedotozine on visceral hypersensitivity was evaluated in conscious rats. One hour after colonic irritation (0.6% acetic acid intracolonically), a 30 mmHg colonic distension was applied for 10 min. Irritation increased the number of abdominal contractions induced by colonic distension (23.4 +/- 4.1 versus 4.8 +/- 1.4 in saline-treated rats, P < 0.001). Facilitation of colonic pain was reversed in a dose-dependent manner by fedotozine ((+)-(-1R1)-1-phenyl-1-[(3,4,5-trimethoxy)benzyloxymethyl]-N ,N-dimethyl-n-propylamine), (+/-)-U-50,488H (trans-(+/-)-3,4-dichloro-N-methyl-N-(2-1-pyrrolidinyl]cyclohexyl)benzen eacetamide) and morphine (respective ED50 values 0.67, 0.51 and 0.23 mg/kg s.c.). The kappa-opioid receptor antagonist, nor-binaltorphimine, abolished the effects of fedotozine and (+/-)-U-50,488H but not those of morphine. Low doses of naloxone (30 microg/kg s.c.) blocked the effect of morphine but not of fedotozine or (+/-)-U-50,488H. After intracerebroventricular administration, morphine was very potent (ED50 1.7 microg/rat), (+/-)-U-50,488H poorly active (58% of antinociception at 300 microg/rat) and fedotozine inactive up to 300 microg/rat. These results show that fedotozine blocks hypersensitive visceral pain by acting on peripheral kappa-opioid receptors in animals.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Abdominal Pain; Analgesics, Opioid; Animals; Antihypertensive Agents; Benzyl Compounds; Dose-Response Relationship, Drug; Injections, Intraventricular; Male; Morphine; Muscle Contraction; Propylamines; Pyrrolidines; Rats; Rats, Sprague-Dawley; Receptors, Opioid, kappa

Topics: Abdominal Pain; Benzyl Compounds; Colonic Diseases, Functional; Humans; Propylamines; Receptors, Opioid, kappa