cp-99994 and resiniferatoxin

1. In SUNCUS: murinus the ultrapotent capsaicin analogue resiniferatoxin (RTX) induced an emetic response in the dose range 1 - 1000 microg kg(-1), s.c. The latency was inversely related to dose and ranged from 41.2+/-4.4 min. (1 microg kg(-1), s.c.) to 2.7+/-0.6 min. (1000 microg kg(-1), s.c.). 2. The emetic response to RTX (10 or 100 microg kg(-1), s.c.) was blocked or markedly reduced by pre-treatment with RTX (100 microg kg(-1), s.c.), 8-OH-DPAT (100 microg kg(-1), s.c.), morphine (2 mg kg(-1), s.c.), neonatal capsaicin (100 mg kg(-1), s.c.) and the NK(1) receptor antagonist CP-99,994 (10 - 20 mg kg(-1), s.c.) but not by the 5-HT(3) receptor antagonist tropisetron (200 microg kg(-1), s.c.). 3. RTX (100 microg kg(-1), s.c.) induced c-fos-like immunoreactivity in the area postrema and parts of the nucleus tractus solitarius. This pattern is consistent with the proposal that the emetic effect is mediated via one or both of these structures and an involvement of substance P is discussed. 4. RTX (10 and 100 microg kg(-1), s.c.) had broad-spectrum antiemetic effects in Suncus as indicated by its ability to block or markedly reduce the emetic response to motion (1 Hz, 4 cm lateral, 10 min.), cisplatin (20 mg kg(-1), i.p.), intragastric copper sulphate (40 mg kg(-1), p.o.), nicotine (10 mg kg(-1), s.c.) and RTX (100 microg kg(-1), s.c.) itself. 5. It is proposed that the site of the anti-emetic effect is in the nucleus tractus solitarius and mechanisms involving the modulation of substance P release are discussed. 6. The general utility of SUNCUS: for investigations of vanilloid receptors is reviewed in the light of the exquisite sensitivity of the emetic reflex in this species to resiniferatoxin.

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Abdomen; Animals; Animals, Newborn; Antiemetics; Behavior, Animal; Capsaicin; Cisplatin; Copper Sulfate; Diterpenes; Dose-Response Relationship, Drug; Female; Indoles; Injections, Intraventricular; Male; Medulla Oblongata; Morphine; Motion Sickness; Nicotine; Piperidines; Proto-Oncogene Proteins c-fos; Serotonin Receptor Agonists; Shrews; Tropisetron; Vagotomy; Vomiting

This paper is the first to describe aspects of the mechanics of retching in the insectivore Suncus murinus (house musk shrew) and in an animal of such a small size (approximately 50 g). In anaesthetised animals using the novel stimulus of mechanical stimulation of the upper gastrointestinal tract as the provocative stimulus the frequency of retching was found to be about 4 retches/s, a much higher frequency than in other species (dog, cat, ferret). These studies show that quantification of retching in Suncus cannot be undertaken using direct observation. The temporal pattern of the emetic response was characterised in conscious Suncus using motion (1 Hz, 5 min) and nicotine (20 mg/kg s.c.). The ultrapotent capsaicin analogue resiniferatoxin (100 micrograms/kg s.c.) was discovered to be highly emetic and comparative studies showed that nicotine and resiniferatoxin induced the most intense responses with episodes (retches and a vomit) occurring every 10-15 s. The retching response to mechanical stimulation in the anaesthetised Suncus was not blocked by a 5-HT3 receptor antagonist (granisetron, 1-5 mg/kg s.c.), a tachykinin NK1 receptor antagonist (CP-99,994 20 mg/kg s.c. dihydrochloride salt (9+) -(2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine) or morphine (2 mg/kg s.c.) but was blocked by the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT 100 micrograms/kg s.c.). Suncus appears to be a suitable animal in which to study the pharmacology of the emetic response to mechanical stimulation of the gut. The results are discussed in the light of studies of the pharmacology of emesis in other species.

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Animals; Digestive System Physiological Phenomena; Diterpenes; Granisetron; Male; Morphine; Motion; Neurokinin-1 Receptor Antagonists; Nicotine; Piperidines; Receptors, Serotonin; Receptors, Serotonin, 5-HT3; Serotonin Antagonists; Serotonin Receptor Agonists; Shrews; Vomiting

These studies have compared the pharmacological profile of two non-peptide human type neurokinin1 (hNK1) receptor selective antagonists, L-741,671 and a quaternised compound L-743,310. In radioligand binding studies L-741,671 and L-743,310 had high affinity for ferret and cloned hNK1 receptors [Ki (nM) ferret 0.7 and 0.1; human 0.03 and 0.06, respectively] but low affinity for rodent NK1 receptors [Ki (nM) 64 and 17, respectively] suggesting that ferret receptors have hNK1-like binding pharmacology. Studies in vivo showed that L-741,671 and L-743,310 had equivalent functional activity in the periphery (ID50s of 1.6 and 2 micrograms/kg i.v., respectively) as measured by inhibition of plasma protein extravasation evoked in the oesophagus of guinea pigs by resiniferatoxin (7 nmol/kg i.v.). Using an in situ brain perfusion technique in anaesthetised rats, L-741,671 was shown to be much more brain penetrant than the quaternary compound L-743,310 which had an entry rate similar to the poorly brain penetrant plasma marker inulin. These compounds thus provided an opportunity to compare the anti-emetic effects of equi-active hNK1 receptor antagonists with and without brain penetration to central NK1 receptor sites. When tested against cisplatin-induced emesis in ferrets, L-741,671 (0.3, 1 and 3 mg/kg i.v.) produced marked dose-dependent inhibition of retching and vomiting but L-743,310 was inactive at 3 and 10 micrograms/kg i.v. In contrast, direct central injection of L-741,671 and L-743,310 (30 micrograms) into the vicinity of the nucleus tractus solitarius or L-743,310 (200 micrograms) intracisternally was shown to inhibit retching and vomiting induced by i.v. cisplatin. L-741,671 and L-743,310 had equivalent functional activity, at the same dose, against cisplatin-induced emesis when injected centrally. These observations indicated that had L-743,310 penetrated into the brain after systemic administration it would have been active in the cisplatin-induced emesis assay and so show that brain penetration is essential for the anti-emetic action of systemically administered NK1 receptor antagonists.

Topics: Animals; Antiemetics; Antineoplastic Agents; Blood Proteins; Brain Chemistry; Cell Line; Cisplatin; Diterpenes; Ferrets; Guinea Pigs; Indoles; Ligands; Male; Neurokinin-1 Receptor Antagonists; Neurotoxins; Piperidines; Radioligand Assay; Receptors, Neurokinin-1; Triazoles; Vomiting

In the present study we characterized the receptor(s) that mediates non-adrenergic non-cholinergic (NANC) contractions of isolated guinea pig cervical trachea, using CP-99,994, a selective neurokinin (NK1) receptor antagonist, and SR-48,968, a selective neurokinin (NK2) receptor antagonist. The activity of these two antagonists was determined against contractions to the selective agonists ([beta Ala8]NKA(4-10) for NK2 and [Sar9,Met(O2)11]SP for NK1) and the nonselective (SP and NKA) NK receptor agonists. CP-99,994 was inactive versus NKA and [beta Ala8]NKA(4-10) but antagonized SP- and [Sar9,Met(O2)11]SP-induced contractions with -log KB values of 5.6 +/- 0.2 and 7.7 +/- 0.2, respectively. SR-48,968 was inactive versus SP and [Sar9,Met(O2)11]SP but was active versus NKA and [beta Ala8]NKA(4-10), yielding -log KB values of 8.4 +/- 0.2 and 9.1 +/- 0.2, respectively. In the presence of 1 microM atropine, 1.4 microM indomethacin, 0.2 microM timolol, and 4 microM thiorphan, electrical field stimulation (16 Hz, 2.0 ms, 50 V for 10 every 30 min) elicited a NANC contractile response which was not significantly altered by CP-99,994 (3 microM) or the nitric oxide synthase inhibitor L-NAME (10 microM) but was completely inhibited by tetrodotoxin (TTX) (1 microM) and was also reduced to 58 +/- 12, 31 +/- 16, 8 +/- 4, and 0% of control by 15, 50, 150, and 1500 nM SR-48,968, respectively. Resiniferatoxin (1 and 10 nM) produced a well-maintained concentration-dependent contraction, which was 57.8 +/- 4.8 and 61.6 +/- 3.8%, respectively, of the carbachol-induced maximum response. Contractions were not significantly modified by L-NAME and were not blocked by TTX (1 microM).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Airway Resistance; Animals; Arginine; Benzamides; Diterpenes; Electric Stimulation; Guinea Pigs; In Vitro Techniques; Male; Neurotoxins; NG-Nitroarginine Methyl Ester; Piperidines; Receptors, Neurokinin-1; Receptors, Neurokinin-2; Tetrodotoxin; Trachea

The present study characterized neurokinin receptor-mediated bronchoconstrictor responses in anesthetized guinea pigs. Thus, we have compared the actions of the selective neurokinin 1 (NK1) (CP-99,994) and neurokinin 2 (NK2) (SR-48,968) receptor antagonists against dose-response curves (DRC) induced by intravenously administered substance P (SP), neurokinin A (NKA), neurokinin B (NKB), beta Ala8-NKA (4-10),Sar9-Met(O2)11SP, and single dose (intravenous) challenge with resiniferatoxin (RTX), a capsaicin-like sensory neurotoxin, leukotriene D4 (LTD4) and antigen. The rank order of potency of the neurokinins for inducing bronchoconstriction was beta Ala8-NKA(4-10) > NKA > Sar9-Met(O2)11Sp > SP >> NKB. The DRC to the selective NK1 agonist Sar9-Met(O2)11SP was shifted to the right 10-fold by the selective NK1 antagonist, CP-99,994 (1 mg/kg, intravenously), but was not shifted by SR-48,968 (3 mg/kg, intravenously). The DRC to the selective NK2 agonist beta-Ala8-NKA(4-10) was shifted to the right 82-fold by the NK2 antagonist, SR-48,968 (1 mg/kg), but was not shifted by CP-99,994 (3 mg/kg, intravenously). SR-48,968 (1 mg/kg) also blocked NKA (3-fold shift) but did not block SP. CP-99,994 failed to produce a significant rightward shift of the DRC to either SP or NKA. However, the combination of 1 mg/kg CP-99,994 and 1 mg/kg SR-48,968 produced significant shifts of the DRCs to SP (> 5-fold) and NKA (> 300-fold). Hypotension induced by NKA and SP was also blocked by this combination.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Benzamides; Bronchial Spasm; Bronchoconstriction; Diterpenes; Dose-Response Relationship, Drug; Drug Interactions; Guinea Pigs; Male; Neurokinin A; Peptide Fragments; Piperidines; Receptors, Neurokinin-1; Receptors, Neurokinin-2; Substance P; Tachykinins