sr-142801 and Disease-Models--Animal

We have previously shown that neurokinin-1 (NK1) receptors predominantly mediate substance P-induced secretion of the non-inflamed rat colonic mucosa in vitro with a gradient in the magnitude of these responses. The aim of this study was to examine the effects of chronic inflammation on the contributions of different neurokinin receptor subtypes to colonic mucosal secretion. Colitis was induced by the intracolonic administration of 2,4,6-trinitrobenzene sulfonic acid in rats, reactivated 6 weeks later. Segments of proximal, mid- and distal colon were stripped of muscularis propria and mounted in Ussing chambers for measurement of short-circuit current. Use of selective agonists suggests that in the chronically inflamed rat colon NK1 receptors play a greater role in neurokinin-mediated mucosal secretion than do either NK2 or NK3. Selective antagonism implies that this is region-specific, with the inflammatory process altering the relative contribution of the neurokinin receptor subtypes within each region of the rat colon.

Topics: Anesthetics, Local; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antipsychotic Agents; Benzamides; Colitis; Disease Models, Animal; Indomethacin; Intestinal Mucosa; Male; Neurokinin A; Neurokinin-1 Receptor Antagonists; Neurotransmitter Agents; Piperidines; Quinuclidines; Rats; Rats, Sprague-Dawley; Receptors, Neurokinin-1; Receptors, Neurokinin-2; Receptors, Neurokinin-3; Receptors, Tachykinin; Stereoisomerism; Substance P; Tetrodotoxin; Trinitrobenzenesulfonic Acid

Postoperative ileus (PI) is a common surgical complication treated mainly with supportive measures. Tachykinins control gastrointestinal motility and modulate somatic and visceral pain sensation; therefore, the effect of tachykinin receptor antagonists in a rat model of PI using NK(1-3) antagonists, SR140333, SR48968, and SR142801, was investigated.. Intestinal transit was measured as Evans blue migration after varied nociceptive stimuli: skin incision (SI), laparotomy (LAP), or laparotomy plus gut manipulation (L + M) in anesthetized rats.. Diethyl ether anesthesia and SI did not influence the intestinal transit of the dye in comparison to untreated animals--UN: 61.17 +/- 5.47, 62.10 +/- 8.30, and 56.70 +/- 4.10 cm, respectively. In contrast LAP and L + M have significantly reduced intestinal motility to 26.40 +/- 2.07 and 9.70 +/- 1.15 cm, respectively. SR140333 (3-30 microg/kg), SR48968 (1-30 microg/kg), and SR142801 (3-10 microg/kg) reversed the additional inhibitory effects of gut manipulation subsequent to LAP dose-dependently, the dye transit returning with the use of the most effective antagonist doses up to 25.28 +/- 1.08, 21.70 +/- 0.19, and 25.0 +/- 1.34 cm. The combinations of submaximal doses of NK(1) and NK(3), NK(2) and NK(3) and NK(1), and NK(2) and NK(3) antagonists were not more effective than a single-agent regimen. On the other hand SR140333 and SR48968 (NK(1) + NK(2) antagonists) acted additively, the intestinal transit reaching 26.60 +/- 0.85 cm. SR140333, SR48968, and SR142801 have not affected the intestinal passage in UN rats or those undergoing SI or LAP.. SR140333, SR48968, and SR142801 exert a salutary action on suppressed gut motility following surgical manipulation of the gut, the combination of NK(1) and NK(2) antagonists being most beneficial.

Topics: Anesthetics, Inhalation; Animals; Antipsychotic Agents; Benzamides; Disease Models, Animal; Ether; Gastrointestinal Motility; Ileus; Male; Neurokinin-1 Receptor Antagonists; Piperidines; Postoperative Complications; Quinuclidines; Rats; Rats, Wistar; Receptors, Neurokinin-2; Receptors, Neurokinin-3; Receptors, Tachykinin

Gastro-oesophageal reflux is a common clinical disorder associated with a variety of respiratory symptoms, including chronic cough and exacerbation of asthma. In this study, the potential role of acid-induced tachykinin release was examined in guinea pigs and rabbits, by examining the effects of the tachykinin NK1 and NK3 receptors antagonists (SR 140333 and SR 142801, respectively) (1-10 mg x kg(-1)) on plasma protein extravasation induced in airways by hydrochloric acid (HCl) infusion in the oesophagus. Guinea pigs were anaesthetised with urethane, while rabbits were subject to neuroleptoanalgesia with hypnorm. Airway vascular leakage was evaluated by measuring extravasation of Evans blue dye. All animals were pretreated with atropine (1 mg x kg(-1) i.p.), propranolol (1 mg x kg(-1) i.p.), phosphoramidon (2.5 mg x kg(-1) i.v.) and saline or tachykinin receptor antagonists (1-10 mg x kg(-1) i.p.). Infusion of 1 N HCl into the oesophagus led to a three- and five-fold increase in plasma extravasation in the main bronchi and trachea, respectively. This increase was largely prevented by the tachykinin NK1 and NK3 receptor antagonists SR 140333 and SR 142801 (1-10 mg x kg(-1)). These results suggest that protein extravasation in the airways, as induced by intraoesophageal HCl infusion, is mainly dependent on the release of tachykinins, and that both NK1 and NK3 tachykinin receptors are involved. The results suggest that HCl-induced sensory nerve stimulation may act in the periphery on intermediate neurons and/or ganglia where NK3 receptors have been shown to play an important role.

Topics: Animals; Asthma; Capillary Permeability; Disease Models, Animal; Esophagus; Female; Gastroesophageal Reflux; Guinea Pigs; Hydrochloric Acid; Instillation, Drug; Male; Neurokinin-1 Receptor Antagonists; Piperidines; Quinuclidines; Rabbits; Receptors, Neurokinin-1; Receptors, Neurokinin-3

To evaluate the roles of spinal neurokinin receptors in the development of persistent nociception and hyperalgesia to thermal and mechanical stimuli induced by subcutaneous (s.c.) bee venom injection, effects of intrathecal (i.t.) pre- or post-treatment with a non-selective antagonist of (NK1/2) receptors, [D-Arg1,D-Trp7,9,Leu11] substance P (spantide), and a selective NK3 receptor antagonist, (S)-(N)-(1-(3-(1-benzoyl-3-(3,4-dichlorophenyl) piperidin-3-yl)propyl)-4-phenylpiperidin-4-yl)-N-methyl acetamide (SR142801) were assessed in conscious rat. Injection of bee venom s.c. into the plantar surface of one hind paw resulted in a pathological pain phenomenon characterized by a 1-2 h single phase of persistent spontaneous nociceptive behaviors (continuously flinching the injected paw) and a 72-96 h profound primary thermal and mechanical hyperalgesia in the injection site and a secondary thermal hyperalgesia in the non-injected hindpaw. Pre-treatment with spantide i.t. at 0.05 microg, 0.5 microg and 5 microg produced a dose-related suppression of the bee venom-induced flinching reflex during the whole time course and the inhibitory rate was 24 +/- 12.60% (35.38 +/- 4.12 flinches/5 min, n=5), 48 +/- 6.75% (24.53 +/- 2.90 flinches/5 min, n=5) and 60 +/- 7.69% (18.88 +/- 3.58 flinches/5 min, n=5) respectively when compared with the saline control group (46.80 +/- 2.60 flinches/5 min, n=5). Post-treatment of spantide i.t. at the highest dose (5 microg) used in the present study 5 min after bee venom injection also produced a 49% suppression of the flinching reflex in the control group [post-spantide vs saline: 19.42 +/- 3.15 (n=5) vs 38.42 +/- 3.25 flinches/5 min (n=5)]. Moreover, i.t. pre-treatment with 5 microg spantide partially prevented the primary and secondary thermal hyperalgesia from occurring, while it did not show any influence on the development of primary mechanical hyperalgesia. Neither the established thermal nor mechanical hyperalgesia identified in the above sites was affected by i.t. post-treatment with the same dose of spantide 3 h after bee venom injection. Pre and post-treatment of SR142801 did not produce any significant effect on the bee venom-induced spontaneous pain and thermal and mechanical hyperalgesia. Our present result suggests that activation of spinal NK1/2 receptors is involved in both induction and maintenance of the persistent spontaneous nociception, while it is only involved in induction of the primary and secondary thermal

Topics: Analgesics; Animals; Bee Venoms; Consciousness; Disease Models, Animal; Hot Temperature; Hyperalgesia; Injections, Subcutaneous; Neurokinin-1 Receptor Antagonists; Nociceptors; Pain Threshold; Physical Stimulation; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, Neurokinin-1; Receptors, Neurokinin-2; Spinal Cord; Substance P

Several observations suggest that tachykinins (substance P, neurokinin A and neurokinin B) are involved in the pathogenesis of pulmonary diseases and elicit several airway responses such as bronchoconstriction and neurogenic inflammation via interactions with specific receptors denoted NK(1), NK(2) and NK(3). We have investigated the effect of a selective antagonist for tachykinin NK(3) receptor, SR 142801 ((R)-(N)-(1-(3-(1-benzoyl-3-(3,4-dichlorophenyl)piperidin-3-yl)propyl)-4-phenylpiperidin-4-yl-N-methylacetamide), on the inflammatory cell recruitment in ovalbumin-sensitized and -challenged mice used as a model of allergic asthma. Twenty hours after the two-ovalbumin challenges, differential cell counts were calculated and indicated that SR 142801 caused a significant decrease in the number of neutrophils and eosinophils. Forty hours after the last ovalbumin exposure, SR 142801 induced a significant decrease in the recruitment of eosinophils. These results suggest that tachykinins and tachykinin NK(3) receptors can interfere with cell recruitment in inflammatory response.

Topics: Animals; Asthma; Bronchoalveolar Lavage Fluid; Cell Count; Disease Models, Animal; Eosinophils; Lymphocytes; Macrophages; Male; Mice; Mice, Inbred BALB C; Neutrophils; Ovalbumin; Piperidines; Receptors, Neurokinin-3

We examined the effect of SR 140333, a nonpeptide NK1 receptor antagonist, FK 888, a peptide NK1 antagonist, and SR 142801, a non-peptide NK3 antagonist, on ear oedema induced by topical application of capsaicin (250 micrograms/ear) in mice. SR 140333 (ED50:39 micrograms/kg, i.v.) dose-dependently inhibited the oedema response to capsaicin, whereas FK 888 (1.0 mg/kg, i.v.) and SR 142801 (3.0 mg/kg, i.v.) had no effect. Furthermore, SR 140333 significantly (p < 0.001) suppressed ear oedema in response to intradermal injection of substance P (SP) (100 pmol/site) by i.v. administration (0.1 mg/kg,) and co-injection (50 pmol/site). In contrast, FK 888 (1.0 mg/kg, i.v. and 500 pmol/site) was ineffective in the response to SP. The present results suggest that the difference in effects of the two NK1 receptor antagonists on the oedema response to capsaicin is due to species differences in affinities for the NK1 receptor in the mouse skin. Moreover, it seems unlikely that the NK3 receptor is involved primarily in capsaicin-induced mouse ear oedema.

Topics: Animals; Binding Sites; Capsaicin; Dipeptides; Disease Models, Animal; Ear Diseases; Edema; Indoles; Injections, Intravenous; Lethal Dose 50; Male; Mice; Piperidines; Quinuclidines; Receptors, Tachykinin; Skin; Stereoisomerism; Structure-Activity Relationship; Substance P