Jean-Louis Junien

Conditioned emotional response in rats enhances colonic motility through the central release of corticotropin-releasing factor.

The effect of a mental stress model corresponding to conditioned fear on cecocolonic motility was evaluated electromyographically in intact and hypophysectomized rats equipped with electrodes implanted in the cecum and proximal colon over a long period and a small polyethylene catheter inserted into the right lateral ventricle of the brain. Intact fasted and fed rats showed an increase of 82.3% and 67.2%, respectively, in colonic spike-burst frequency when placed for 30 minutes in a box in which they had previously received electrical shocks in their feet. Intracerebroventricular administration of corticotropin-releasing factor (0.5 micrograms/kg) mimicked the effects of mental stress and increased cecocolonic spike-burst frequency by 75.8%. The specific corticotropin-releasing factor receptor antagonist alpha-helical CRF9-41 given intracerebroventricularly (5 micrograms/kg) prevented both the effects of mental stress and corticotropin-releasing factor (0.5 micrograms/kg intracerebroventricularly) on colonic spike-burst frequency. In contrast, diazepam (0.5 mg/kg IM) suppressed colonic hypermotility induced by mental stress but not that resulting from intracerebroventricular injection of corticotropin-releasing factor (0.5 micrograms/kg). Increased colonic spike-burst frequency induced either by stress or by central administration of corticotropin-releasing factor was not prevented by hypophysectomy. It was concluded that mental stress increases the frequency of cecocolonic spike-burst activity and that these effects are related to the central release of corticotropin-releasing factor because they are blocked by a corticotropin-releasing factor antagonist and reproduced by intracerebroventricular administration of corticotropin-releasing factor. Moreover, mental stress-induced colonic motor alterations are mediated by the autonomic nervous system rather than by the hypothalamopituitary axis because they are not abolished by hypophysectomy.

JO 1784, a potent and selective ligand for rat and mouse brain σ-sites

Abstract— JO 1784 ((+)‐cinnamyl‐1‐phenyl‐1‐N‐methyl‐N‐cyclopropylene) is a potent ligand for (+)‐[3H]SKF 10,047 (2′‐hydroxy‐5,9‐dimethyl‐2‐allyl‐6,7‐benzomorphan) binding sites in rat brain membrane preparations with an IC50 of 39 ± 8 nM, which is comparable to that of haloperidol. The stereoisomer of JO 1784 is ten fold less potent. When administered to mice i.p. or p.o. JO 1784 displaced (+)‐[3H]SKF 10,047 (5 μCi i.v.) from its sites in the brain with ID50 values of 1.2 and 3.5 mg kg−1, respectively. The high selectivity of JO 1784 for the σ‐binding site was assessed by its lack of significant affinity for more than 20 other sites including those for phencyclidine.

Autoradiographic localization of sigma opioid receptors in the gastrointestinal tract of the guinea pig

The distribution of sigma and phencyclindine binding sites in the gastrointestinal tract of the guinea pig was studied by autoradiography after in vitro incubation of tissue slices with (+)3H-SKF 10,047 and 3H-1-1-[(2-thienyl)cyclohexyl] piperidine to locate sigma and phencyclidine receptors, respectively. A dense distribution of sigma binding sites was observed in the mucosa and in the submucosal plexus, particularly at the level of the fundus and duodenum. Muscular layers were only marginally labeled. No phencyclidine binding site could be demonstrated in any area. This selective distribution suggests a functional role of sigma receptors mainly in the control of endocrine or exocrine secretions, or both.

Evidence for a non-opioid sigma binding site in the guinea-pig myenteric plexus

The presence of a binding site to (+)-(3H)SKF 10,047 was demonstrated in a guinea-pig myenteric plexus (MYP) membrane preparation. Specific binding to this receptor was saturable, reversible, linear with protein concentration and consisted of two components, a high affinity site (KD = 46 +/- 5 nM; Bmax = 3.4 +/- 0.5 pmole/g wet weight) and a low affinity site (KD= = 342 +/- 72 nM; Bmax = 22 +/- 3 pmole/g wet weight). Morphine and naloxone 10(-4) M were unable to displace (+)-(3H)SKF 10,047 binding. Haloperidol, imipramine, ethylketocyclazocine and propranolol were among the most potent compounds to inhibit this specific binding. These results suggest the presence of a non-opioid haloperidol sensitive sigma receptor in the MYP of the guinea-pig.

Interactions of trimebutine with guinea-pig opioid receptors.

Affinities of trimebutine (TMB) and N‐desmethyl trimebutine (NDTMB) for mu, delta and kappa opioid receptor subtypes have been examined using specific 3H‐ligands and guinea‐pig membrane. TMB and NDTMB showed a relative higher affinity for the mu receptor subtype although they were, respectively, 30‐and 48‐fold less active than morphine. The receptor selectivity index for mu, delta and kappa were 100:12:14ṁ4 for TMB, 100:32:25 for NDTMB and 100:5:5 for morphine. The sodium shift ratio was 14 for TMB, 10 for NDTMB and 37 for morphine. These data show that (unlike morphine, a pure mu agonist) TMB and NDTMB can be classified as weak opioid agonists and confirm that peripheral opioid receptors mediate their gastrointestinal motility effects.

Opposite effects of κ-opioid agonists on gastric emptying of liquids and solids in dogs

Abstract The influence of oral (p.o.) administration of κ-(U-50488, tifluadom) and μ- (morphine, DAGO) opioid substances on gastric emptying of liquids and solids in a standard canned dog food meal was evaluated using a double-radiolabeled technique in dogs fitted with gastric cannulas. One hour after feeding, 28.6% ± 3.6% (mean ± SD) of the solid phase and 27.1% ± 8.6% of the liquid phase of the meal had been emptied. Both U-50488 and tifluadom given orally (0.01–0.1 mg/kg) significantly increased (p

Selective stimulation of colonic motor response to a meal by σ ligands in dogs

The influence of central vs. peripheral administration of sigma ligands (dl- and l-N-allylnormetazocine, 1-3-di-o-tolylguanidine, (+) cinnamyl-1-phenyl-1-N-methyl-N-cyclopropylene and phencyclidine on colonic motility was investigated in fasted and fed dogs equipped with strain-guage transducers implanted on proximal and transverse colon. When injected intravenously at a dose of 0.25 mg/kg just before feeding, dl- or d-N-allylnormetazocine, 1-3-di-o-tolylguanidine, and (+) cinnamyl-1-phenyl-1-N-methyl-N-cyclopropylene (but not phencyclidine) enhanced the colonic motor response to a meal by increasing the 0-4-hour motility indexes from 64.1%-159.3% in both the proximal and transverse colon but had no effect on colonic motility in fasted animals or animals injected intracerebroventricularly. The motor-stimulatory effects of d-N-allylnormetazocine (1 mg/kg), 1-3-di-o-tolylguanidine (0.25 mg/kg), and (+) cinnamyl-1-phenyl-1-N-methyl-N-cyclopropylene (1 mg/kg) were abolished after previous treatment with haloperidol (0.5 mg/kg, intravenous) but not after sulpiride (0.1 mg/kg) or (+) R-(+)-8-chloro-2,3,4,5-tetrahydro-3- methyl-5-phenyl-1-H-3-benzozepine-OH. Prazosin (0.1 mg/kg, intravenous) and 1-methyl-3-(2-indolyl)amino-5-phenyl-3H-1,4-benzodiazepin-2-one (0.01 mg/kg) also suppressed the enhancement of the colonic motor response to eating induced by d-N-allylnormetazocine, 1-3-di-o-tolylguanidine, and (+)cinnamyl-1-phenyl-1-N-methyl-N-cyclopropylene whereas naltrexone did not affect their effects. It is concluded that d-N-allylnormetazocine, 1-3-di-o-tolylguanidine, and (+)cinnamyl-1-phenyl-1-N-methyl-N-cyclopropylene stimulate the postprandial colonic motility in dogs by acting selectively on sigma receptors located peripherally and probably by affecting the release of cholecystokinin octapeptide through a central adrenergic mechanism.

Peripheral antagonistic action of trimebutine and κ opioid substances on acoustic stress-induced gastric motor inhibition in dogs

The effects of intracerebroventricular (i.c.v.), intravenous (i.v.) and oral (p.o.) administration of trimebutine on the gastric motor inhibition induced by acoustic stress were investigated in fasted dogs fitted with strain-gauge transducers on the antrum and proximal jejunum. Started 40-50 min after the last migrating motor complex, a 1 h acoustic stress delayed by 111% the occurrence of the next gastric migrating motor complex without affecting the jejunal motor pattern. This inhibition of gastric migrating motor complex induced by acoustic stress was abolished by previous p.o. administration of trimebutine (1 mg/kg) but not by its i.v. (0.1 mg/kg) or i.c.v. (0.01 mg/kg) injection. The trimebutine blockade of gastric motor alterations induced by acoustic stress was suppressed after previous i.v. treatment with MR 2266 (0.3 mg/kg) but was unaffected by naloxone (0.3 mg/kg). Furthermore oral administration of U-50488H (10 micrograms/kg) and ethylketocyclazocine (10 micrograms/kg) respectively abolished and reduced the acoustic stress-induced delay of the occurrence of the gastric migrating motor complex. We concluded that trimebutine is able to antagonize the gastric motor disturbances induced in dogs by acoustic stress, probably by acting selectively on peripheral kappa receptors located in the wall of the proximal gut and directly stimulated from a mucosal site.

Antagonism of Stress‐Induced Gastric Motor Alteration and Plasma Cortisol Release by Fedotozine (JO 1196) in Dogs

The effects of fedotozine (a new dimethyl propylamine derivative) on gastric motor inhibition and plasma cortisol increase induced by acoustic stress were investigated in fasted dogs fitted with strain‐gauge transducers on the antrum and proximal jejunum and an implanted jugular catheter. Stress was induced by 1 hour of music (≤90 dB) played through earphones. Starting 40 to 50 minutes after the last migrating motor complex (MMC), acoustic stress delayed by 131% the next gastric MMC, whereas intestinal motility was unaffected. Plasma cortisol increased (p < 0.05) by 516%, 30 minutes after the beginning of noise. The inhibition of gastric MMC as well as the hypercortisolemia induced by acoustic stress were reduced in a dose‐related manner or abolished by previous oral administration of fedotozine (0.1–1 mg/kg) but not by intravenous injection (0.1–0.5 mg/kg). The effect of fedotozine was abolished after previous intravenous treatment with MR 2266 (0.1 mg/kg). Only the motor effects were suppressed by naloxone (0.1 mg/kg i.v.), which induced a significant (p < 0.05) increase in plasma level. Bilateral truncal vagotomy, which suppressed the effects of acoustic stress on gastric motility but not on plasma cortisol, suppressed the antagonistic influence of fedotozine on hypercortisolemia. We conclude that fedotozine administered orally reduces both stress‐induced gastric motor alterations and hypercortisolemia, probably by acting directly on K receptors present in the intestinal wall that activate vagal afferent fibers interacting, at the central nervous system level, with factors responsible for the gastric and endocrine alterations induced by stress.

Regional differences in the effect of N-[1-(2-benzo[b]thiophenyl)cyclohexyl]piperidine (BTCP) on extracellular dopamine levels: An in vivo microdialysis study

N-[1-(2-Benzo[b]thiophenyl)cyclohexyl]piperidine (BTCP) is a phencyclidine derivative highly selective for the dopamine (DA) uptake complex. Its effect on extracellular DA levels was studied by in vivo microdialysis on freely moving rats. In the striatum, BTCP induced a dose-dependent increase in DA levels, without affecting DA metabolites. In the nucleus accumbens, a lower increase in DA was observed, but with concomitant decreases in 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). These experiments show that the effects of BTCP on extracellular DA levels are significantly different on extrapyramidal and mesolimbic dopaminergic terminals.