neurokinin-a and Colonic-Diseases--Functional

Menarini Richerche is developing nepadutant, an NK2 antagonist, for the potential treatment of asthma and irritable bowel syndrome. The compound is in phase IIa trials in Belgium and Sweden for both these indications [359518].

Topics: Animals; Asthma; Bronchodilator Agents; Colonic Diseases, Functional; Humans; Neurokinin A; Peptides, Cyclic; Receptors, Neurokinin-2; Structure-Activity Relationship

The tachykinins substance P and neurokinin A participate in the regulation of gastrointestinal motility, secretion, vascular permeability and pain sensitivity. Advances made during the past two years corroborate a causal involvement of tachykinins in inflammation-induced disturbances of gut function, such as dysmotility, secretory diarrhoea, oedema and hyperalgesia. It would therefore appear that tachykinin receptors, which in the digestive system are expressed in a cell-specific manner, represent attractive targets for novel therapeutics in gastroenterology.

Topics: Animals; Colonic Diseases, Functional; Digestive System; Digestive System Physiological Phenomena; Gastrointestinal Diseases; Gastrointestinal Motility; Humans; Inflammatory Bowel Diseases; Neurokinin A; Receptors, Neurokinin-1; Receptors, Neurokinin-2; Receptors, Neurokinin-3; Receptors, Tachykinin; Substance P

The potent neurokinin receptor 1 (NK1) antagonist SR-140333 has previously been shown to reduce castor oil-induced secretion in animal models. The importance of tachykinins in neuroimmune control of secretion and the effect of SR-140333 on key points in this pathway were elucidated in the present study to determine the type of intestinal dysfunction best targeted by this antagonist. Rat colonic secretion and substance P (SP) release were determined in vitro with the use of Ussing chamber and enzyme immunoassay techniques. NK1 receptors played a secretory role as receptor agonists stimulated secretion and SR-140333 antagonized the response to SP response (pK(b) = 9.2). Sensory fiber stimulation released SP and evoked a large secretion that was reduced by 69% in the presence of SR-140333 (10 nM). Likewise, mastocytes also released SP. The subsequent secretory response was reduced by 43% in the presence of SR-140333 (50 nM). SP was also released from granulocytes; however, this did not cause secretion. Functional NK3 receptors were present in the colon as senktide stimulated secretion, an effect that was increased during stress. We conclude that NK3 receptors may play a role in stress-related disorders, whereas NK1 receptors are more important in mast cell/afferent-mediated secretion.

Topics: Animals; Benzamides; Capsaicin; Colon; Colonic Diseases, Functional; Electric Stimulation; Male; Mast Cells; Neurokinin A; Neurokinin-1 Receptor Antagonists; Peptide Fragments; Piperidines; Quinuclidines; Rats; Rats, Inbred Strains; Receptors, Neurokinin-1; Receptors, Neurokinin-2; Receptors, Neurokinin-3; Stress, Physiological; Substance P

Tachykinins participate in somatic pain and intestinal motility control. The role of tachykinin receptors in both colonic motor disturbances and visceral pain (abdominal contractions as an index of visceral pain) induced by rectal distension were investigated.. Rats were surgically prepared with electrodes implanted on the proximal colon and the abdominal striated muscles. Catheters were implanted in lateral ventricles of the brain. Rectal distension was performed by inflation of a balloon (0.1-1.6 mL) rectally inserted. CP-96,345 and RP-67,580 (neurokinin [NK] 1 antagonists) and SR-48,968 (NK2 antagonist) were injected intraperitoneally (IP) or intracerebroventricularly (ICV) 20 minutes before distension. GR-73,632 and GR-64,639 (NK1, NK2 agonists) were infused intravenously at 0.15 micrograms.kg-1.min-1.. Rectal distension evoked a significant inhibition of colonic motility and an increase in abdominal contractions. CP-96,345 injected ICV (0.2-0.8 mg/kg) or IP (5-10 mg/kg) and RP-67,580 (0.2 mg/kg IP) eliminated distension-induced colonic inhibition but did not affect abdominal response. SR-48,968 did not affect colonic response but significantly reduced visceral pain (0.4, 0.8 mg/kg ICV: 5-10 mg/kg IP). GR-73,632 enhanced the rectal distension-induced colonic inhibition, whereas GR-64,349 induced a greater abdominal response.. NK1 receptors mediate the rectocolonic inhibitory reflex, whereas NK2 receptors participate in visceral pain; both responses involve central structures.

Topics: Abdomen; Animals; Benzamides; Biphenyl Compounds; Colon; Colonic Diseases, Functional; Gastrointestinal Motility; Hypnotics and Sedatives; Indoles; Isoindoles; Male; Neurokinin A; Peptide Fragments; Piperidines; Rats; Rats, Wistar; Receptors, Neurokinin-1; Receptors, Neurokinin-2; Receptors, Tachykinin; Rectum; Substance P; Tachykinins