sincalide and igmesine

Previous studies from our laboratory have demonstrated that low doses of selective sigma (sigma) ligands potentiate the response of pyramidal neurones to N-methyl-D-aspartate (NMDA) in the CA3 region of the rat dorsal hippocampus. It has also been found that the neuropeptide cholecystokinin (CCK) is involved in the effects induced by sigma ligands on colonic motility. The present experiments were undertaken to determine if this interaction is also present in the rat dorsal hippocampus. Using microiontophoresis and in vivo extracellular recordings of rat CA3 dorsal hippocampus pyramidal neurones, we assessed the effects of CCKA and CCKB receptor antagonists on the potentiation of the NMDA response, induced by the intravenous administration of low doses of the sigma ligands 1,3-di(2-tolyl)guanidine (DTG), (+)-pentazocine and JO-1784. The potentiation of the NMDA response induced by these sigma ligands was abolished by the selective CCKA receptor antagonist SR 27897, but not by the CCKB antagonist Cl-988. CCK-8S, applied with a low current, insufficient to induce by itself an increase of the firing activity, markedly potentiated the response of NMDA without affecting significantly that of quisqualate. SR 27897, but not Cl-988, significantly reduced the potentiation of the NMDA response by CCK-8S. These results suggest the existence of a functional interaction between CCK and sigma receptor-mediated effects in the dorsal hippocampus.

Topics: Animals; Cholecystokinin; Cinnamates; Cyclopropanes; Drug Synergism; Electrophysiology; Hippocampus; Hormone Antagonists; Indoleacetic Acids; Male; N-Methylaspartate; Pentazocine; Rats; Rats, Sprague-Dawley; Receptors, sigma; Sincalide; Thiazoles

1. The role of dopamine in the genesis of corticotropin releasing factor (CRF)- and emotional stress (ES)-induced stimulation of colonic motility, as well as the mechanism of antagonistic action of cholecystokinin octapeptide (CCK-8s) and igmesine (alpha sigma receptor ligand, formerly JO 1784) on dopamine-induced colonic hypermotility, have been investigated in the rat. 2. ES and i.c.v. injection of CRF (0.5 microgram kg-1) increased the frequency of colonic spike bursts by 63% and 114%, respectively. Prior i.c.v. administration of (+)-SCH 23390 (a D1 receptor antagonist, 10 micrograms kg-1) significantly (P < 0.05) reduced the CRF- and ES-induced increase in colonic spike burst; whereas, sulpiride (a D2 receptor antagonist, 10 micrograms kg-1) blocked the CRF-induced stimulation of colonic spike bursts but had no effect on the colonic response to stress. 3. I.c.v. injection of dopamine (100 micrograms kg-1), increased colonic spike burst frequency by 54%. (+)-SKF 38393 (5 micrograms kg-1), a selective D1 receptor agonist, and quinpirole (5 micrograms kg-1), a selective D2 receptor agonist, increased colonic spike burst frequency by 71% and 70% respectively. CCK-8s (0.1 microgram kg-1) and igmesine (0.1 microgram kg-1) injected i.c.v. completely prevented the stimulatory effects of dopamine, (+)-SKF 38393 and quinpirole. 4. Previous i.c.v. injection of devazepide, a CCKA receptor antagonist, (10 micrograms kg-1) antagonized the inhibitory effects of both CCK-8s and igmesine injected i.c.v. on dopamine-induced colonic hyperkinesia. 5. These results show that CRF stimulates colonic motility through activation of central dopaminergic mechanisms in response to stress; furthermore, CCK-8s inhibits dopamine-induced colonic hyperkinesia through a mechanism involving D1 and D2 receptors. The sigma receptor ligand igmesine, blocks the CRF and ES-induced colonic hyperactivity via an interaction with central CCK mechanisms.

Topics: Action Potentials; Animals; Benzazepines; Benzodiazepinones; Cholecystokinin; Cinnamates; Colon; Corticotropin-Releasing Hormone; Cyclopropanes; Devazepide; Dopamine; Dopamine Agents; Dopamine Antagonists; Gastrointestinal Motility; Male; Muscle, Smooth; Rats; Rats, Wistar; Sincalide; Stimulation, Chemical; Stress, Psychological; Sulpiride

The effects of neuropeptide Y (NPY), sigma ligand (JO 1784) and sulfated cholecystokinin octapeptide (CCK8s) on emotional stress (ES) and corticotropin-releasing hormone (CRH)-induced colonic hypermotility were evaluated in rats equipped with chronically implanted electrodes on the colon and a small catheter into the lateral ventricle of the brain. A 139% (97-172%) increase in colonic spike burst frequency was observed in rats placed in a test cage in which they had previously received electric footshocks, an event assimilated to an ES. Intracerebroventricular injection of CRH (0.5 microgram/kg) mimicked the effects of ES by increasing colonic spike burst frequency by 89.0%. Given i.c.v., both JO 1784 (0.1 microgram/kg) and NPY (0.15 microgram/kg) blocked these stimulatory effects. Similarly, i.c.v. administration of CCK8s (0.1 microgram/kg) abolished both ES and CRH stimulated colonic motility, an effect reproduced by central injection of JMV 180, a cholecystokinin (CCK) derivative with high affinity for CCKA receptors, (1 microgram/kg), but not by JMV 170, a CCK derivative with low affinity for CCKA receptor at similar or higher dose. BMY 14802 (a sigma receptor antagonist) injected s.c. (1 mg/kg) abolished the antagonistic effects of JO 1784 and NPY on the ES-induced colonic hyperkinesia. Injected i.c.v., devazepide (L 364,718), a CCKA receptor antagonist, at 0.1 and 1 microgram/kg, abolished the effect of both JO 1784 and NPY; by contrast L365,260, a CCKB antagonist, required a dose of 10 micrograms/kg to block the antagonistic effect of NPY and JO 1784.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Cinnamates; Colon; Cyclopropanes; Drug Interactions; Electrophysiology; Gastrointestinal Motility; Injections, Intraventricular; Male; Neuropeptide Y; Rats; Rats, Inbred Strains; Receptors, Cholecystokinin; Receptors, Opioid; Receptors, sigma; Sincalide; Stress, Physiological