A proposal for the classification of sigma binding sites.
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Binding Sites↗
Biomedical subjects
J L Junien
Publications and source records attributed to J L Junien.
Involvement of central dopamine and D1 receptors in stress-induced colonic motor alterations in rats.
The role of central versus peripheral influence of dopamine (DA) in the genesis of emotional stress (ES) induced by fear to receive electric footshocks on colonic motility was evaluated in rats equipped with implanted electrodes on the proximal colon. In control rats, the frequency of colonic spike bursts increased from 7.5 +/- 1.9 to 16.0 +/- 2.1 per 10 min when the rats were placed in a test box where they had previously received electric footshocks. This increase induced by ES was significantly p less than 0.05, reduced by previous ICV or IP administration of (+)SCH 23390 (a D1 receptor antagonist) at doses of 10 and 100 micrograms/Kg, respectively. Although sulpiride (a D2 antagonist) injected ICV or IP at similar doses had no effect on the ES-induced increase in the frequency of colonic spike bursts. DA (100 micrograms/kg), and the selective D1 (SKF 38383) or D2 (quinpirole) receptor agonist injected ICV at a dose of 5 micrograms/kg also increased significantly by 48.7, 54.8, and 68.7%, respectively, the colonic spike burst frequency whereas they are inactive when injected IP at similar and higher doses. These results suggest that, in rats, (a) emotional stress stimulates colonic motility through the stimulation of dopaminergic neurons involving D1 receptors and (b) exogenous activation of central D1 and D2 receptors similarly stimulate colonic motility by increasing the occurrence of colonic spike bursts.
2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
Central neuropeptide Y and the sigma ligand, JO 1784, reverse corticotropin-releasing factor-induced inhibition of gastric acid secretion in rats.
1. The central interactions between the sigma ligand, JO 1784, [(+)-N-cyclopropylmethyl-N-methyl-1,4-diphenyl-1-ethylbut-3- en-1-ylamine hydrochloride], or neuropeptide Y (NPY) and corticotropin-releasing factor (CRF)-induced inhibition of gastric acid secretion were investigated in rats anaesthetized with urethane. Drugs were injected intracisternally (i.c.) or into specific hypothalamic nuclei. Gastric acid secretion was measured by the flushed technique under basal and pentagastrin (10 micrograms kg-1 h-1, i.v.) stimulated conditions. 2. Intracisternal injection of CRF (10 micrograms), bombesin (0.1 microgram) and human recombinant interleukin-1 beta (hIL-1 beta, 0.1 microgram) inhibited gastric acid response to pentagastrin by 72%, 56% and 62%, respectively. NPY (0.5 microgram) or JO 1784 (0.5 microgram) injected i.c. did not alter acid secretion but completely prevented the inhibitory effect of CRF. The antagonistic effect of NPY and JO 1784 against CRF was dose-related (0.01-0.5 microgram) and peptide-specific since NPY and JO 1784 did not alter the antisecretory action of bombesin or hIL-1 beta. 3. The putative sigma receptor antagonist, BMY 14802, (1 mg kg-1, s.c.) did not influence pentagastrin-stimulated acid secretion nor CRF-induced inhibition of gastric acid secretion; however, BMY 14802 administered s.c. 20 min before JO 1784 or NPY, abolished the antagonistic effect of both JO 1784 and NPY. 4. CRF (3 micrograms) microinjected into the hypothalamic paraventricular nucleus (PVN) and the lateral hypothalamus (LH) inhibited pentagastrin-stimulated gastric acid secretion by 61% and 51%; NPY (0.03 micrograms) or JO 1784 (0.03 micrograms) microinjected into the PVN had no effect by themselves but blocked CRF antisecretory action.There were more VPBs (220 +/- 75), a higher incidence of VT (60%) and more episodes of VT (11.5 +/- 6.0 compared to 0.7 +/- 0.3 episodes in the preconditioned dogs not given L-NAME); none of the animals survived reperfusion (incidence of VF 100%). The improvement in the severity of the degree of inhomogeneity which resulted from preconditioning was abolished by L-NAME administration.5. L-NAME itself elevated blood pressure (from 96 +/- 5 mmHg diastolic to 119 +/- 7 mmHg), reduced heart rate (from 155 +/- 7 to 144 +/- 4 beats min-') but did not change LVEDP, LVdP/dt,,,,, coronary blood flow, ST-segment elevation or the degree of inhomogeneity of conduction. When given 10 min before the prolonged coronary artery occlusion in dogs not subjected to preconditioning, L-NAME had no significant effect on the severity of arrhythmias except for more periods of VT (a mean of 11.7 +/- 4.7 episodes per dog).6. It is concluded from these studies that the generation of nitric oxide contributes to the marked antiarrhythmic effects of preconditioning in the canine myocardium, probably through elevation of cyclic GMP.
Animals↗
Pharmacological evaluation of JO 1870: relation to the potential treatment of urinary bladder incontinence.
The effect of p.o. administered JO 1870 [(-)-1-(p-chlorophenyl)-N,N- dimethyl-1-ethyl(4-phenyl)-but-3-en-1-ylamine, hydrochloride] on the urinary bladder cystometrogram has been investigated in the unanesthetized rat. The effects of JO 1870 have been compared with those of morphine and reference drugs currently used for the treatment of urinary incontinence in humans. JO 1870 (2.5-25 mg/kg) dose-dependently increased the bladder capacity and the threshold pressure responsible for urination. These effects were antagonized by the i.v. administration of naloxone (0.2 mg/kg). In comparison, morphine (2.5-25 mg/kg) moderately increased urinary volume and threshold pressure. Different anticholinergic drugs (propantheline bromide, 10 mg/kg; terodiline, 25 mg/kg; dicyclomine, 25 mg/kg) had no significant effects on either parameter and the antidepressant clomipramine (25 mg/kg) decreased both. In vitro, JO 1870 specifically displaced [3H]-[D-Ala2,MePhe4,Gly5-(ol)]enkephalin from binding sites in guinea pig whole-brain membranes and rat thalamus; the sodium shift ratio obtained from [3H]naloxone binding was 16. These results suggest that JO 1870 has some opioid agonist activity. JO 1870 (2.5-300 mg/kg) had few effects on cardiorespiratory, gastrointestinal or nociceptive systems in rats. Together, these results indicate that JO 1870 is a nonanticholinergic agent that potently increases bladder capacity, likely through an opioid mechanism, and may have potential use in the treatment of urinary incontinence.
Animals↗
Neuropeptide Y and sigma ligand (JO 1784) suppress stress-induced colonic motor disturbances in rats through sigma and cholecystokinin receptors.
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)
Animals↗
[Trimebutine. Pharmacology, recent concepts about its mechanism of action, therapeutic results].
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Clinical Trials as Topic↗
Purification and biochemical characterization of dog gastric lipase.
A lipase was found to be present in dog stomach which appeared to be more abundant in the fundic than in the pyloric mucosa. Dog gastric lipase was extracted by soaking the gastric tissue and further purified after cation exchange, anion exchange and gel-filtration using fast protein liquid chromatography. The amino-acid composition, N-terminal amino-acid sequence, substrate specificity, interfacial and kinetic behavior and inactivation by sulfhydryl reagents were determined and compared with those of human and rabbit gastric lipases. We report for the first time that a gastric lipase is 13 times more active on long-chain than on short-chain triacylglycerols at pH 4.0, reaching a maximal specific activity of 950 U/mg on Intralipide emulsion.
Amino Acid Sequence↗
JO1784, a novel sigma ligand, potentiates [3H]acetylcholine release from rat hippocampal slices.
JO1784, a potent and specific sigma ligand, potentiated the KCl-evoked release of [3H]acetylcholine (ACh) from rat hippocampal slices superfused in vitro at 10 and 30 microM. This effect was stereospecific and was antagonized by the presence of haloperidol (0.3 microM). Under similar conditions, (+)-SKF 10,047 also had a potentiating effect whereas di-o-tolyl-guanidine had an inhibitory effect. Phencyclidine was devoid of activity up to a concentration of 30 microM. These results show that sigma compounds display differential effects on evoked [3H]ACh release in rat hippocampal slice preparations.
Acetylcholine↗
Evidence for an anti-amnesic effect of JO 1784 in the rat: a potent and selective ligand for the sigma receptor.
JO 1784 ((+)-N-Cyclopropyl-methyl-N-methyl-1,4-diphenyl-1-yl-but-3-en-1-ylami ne, hydrochloride), has been recently described as a selective ligand for the sigma receptor with an IC50 of 39 +/- 8 nM28. In the present study the effects of JO 1784 on experimental induced amnesia were investigated using one trial passive avoidance task in rats. Amnesia was produced by injecting scopolamine (1 mg/kg i.p.) 30 min before the second session (T2) on day 2 of the passive avoidance task. The anti-amnesic effect of JO 1784 was compared with other typical and atypical psychotropic drugs which interact at the sigma and or the phencyclidine site. JO 1784 was studied at 5 doses; 0.0625, 0.25, 1.0, 4.0 and 16.0 mg/kg i.p. ((+)-3-(3-hydroxyphenyl)-N-1-(propyl)piperidine ((+)-3-PPP). Rimcazole, (+)-N-allylnormetazocine ((+)-NANM), 1,3-di(2-tolyl) guanidine (DTG) were studied at 4 doses; 0.25, 1.0, 4.0 and 8.0 mg/kg i.p. All drugs were administered 60 min before the test (T2) on day 2 i.e. 30 min before scopolamine. Piracetam (1000 mg/kg p.o.) administered in the same test conditions was used as a reference compound in each experiment. Of the drugs investigated JO 1784 (0.25, 1.0, 4.0 and 16.0 mg/kg i.p.), (+)-3-PPP (0.25, 1.0 and 4.0 mg/kg i.p.), DTG (1.0, 4.0 and 8.0 mg/kg) and piracetam significantly reversed scopolamine induced amnesia on day 3 (T3). At the lower dose, JO 1784 (0.0625 mg/kg) failed to reverse the amnesic effects of scopolamine on day 3. These results suggest that JO 1784 the selective sigma ligand, may be beneficial in amnesic status.
Amnesia↗
N-methyl-D-aspartate receptor complex modulation by neuropeptide Y and peptide YY in rat hippocampus in vitro.
Neuropeptide Y (NPY) and peptide YY (PYY) are known to bind with high affinity to sigma (sigma) and phencyclidine (PCP) binding sites in rat brain. The functional significance of these results was assessed by testing both peptides in an in vitro bioassay system used for studying the N-methyl-D-aspartate (NMDA) receptor and consisting of rat hippocampal slices preloaded with [3H]noradrenaline (NA) and maintained under superfusion. The addition of NMDA in the superfusion medium induced an efflux of [3H]NA from the slices and the presence of NPY and PYY produced an enhancement of the stimulating effect. These results suggest that NPY and PYY could have a modulatory role at the NMDA receptor complex through an interaction with the sigma and/or PCP receptor.
Animals↗
Effects of sigma receptor ligands on schedule-controlled behavior of rats: relation to sigma and PCP receptor binding affinity.
Eleven drugs were examined for their ability to inhibit sigma and phencyclidine (PCP) receptor binding, as labelled by (+)[3H]-R-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine ((+)-3-PPP), [3H]ditolylguanidine (DTG), (+)[3H]N-allylnormetazocine (NANM) and [3H]1-(1-(2-thienyl)cyclohexyl)piperidine (TCP), in membrane preparations from whole rat brain. The same drugs were studied for their effects under a fixed-ratio (FR) schedule of food reinforcement in rats. The relative potency order of the drugs for decreasing FR responding was: haloperidol greater than (+)-3-PPP greater than (-)NANM greater than BMY 14802 greater than PCP greater than (+)NANM greater than DTG greater than rimcazole greater than JO 1783 greater than JO1784 greater than (-)butaclamol. The binding affinities of all 11 drugs for either the [3H]DTG, (+)[3H]-3-PPP, (+)[3H]NANM or [3H]TCP site did not correlate significantly with the potencies of the same drugs for decreasing FR behavior. Rimcazole, (+)-3-PPP and haloperidol, at behaviorally inactive doses, were studied for their effects as antagonists of the rate-decreasing effects of JO 1784, DTG and (+)NANM: rimcazole attenuated the effects of DTG and (+)NANM but not JO 1784; (+)-3-PPP attenuated the effects of (+)NANM but not JO 1784 and DTG; and haloperidol was devoid of antagonistic actions. Moreover, BMY 14802 did not attenuate the rate-decreasing effects of (+)-3-PPP. These results further indicate that it is difficult to distinguish between purported sigma agonist and antagonist drugs.
Animals↗
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.
Animals↗
Neuropeptide Y and sigma ligand (JO 1784) act through a Gi protein to block the psychological stress and corticotropin-releasing factor-induced colonic motor activation in rats.
The effects of neuropeptide Y and sigma ligands (d-NANM and JO 1784) on corticotropin-releasing factor (CRF) and psychological stress-stimulated caecal and colonic motility were evaluated by electromyography in rats equipped with chronically implanted electrodes on the caecum and proximal colon and a small catheter into the right lateral ventricle of the brain. Exposure to a psychological stress for 30 min increased significantly (P less than 0.05) the frequency of caecal and colonic spike bursts, an effect which was mimicked by intracerebroventricular administration of CRF (300 ng/kg). Injected intracerebroventricularly, 30 min prior to the psychological stress or intracerebroventricular administration of CRF, neuropeptide Y (150 ng/kg) abolished the excitatory effect on caeco-colonic motility. Similarly, prior administration of d-NANM (100 ng/kg) and JO 1784 (50 ng/kg) abolished the caeco-colonic hypermotility induced by psychological stress and intracerebroventricular injection of CRF. Four days after intracerebroventricular administration of pertussis toxin (150 ng/kg), both neuropeptide Y and JO 1784, when administered centrally, were unable to antagonize the stress-induced hyperkinesia. It is concluded that central administration of neuropeptide Y and sigma ligands abolish the stimulatory effects of psychological stress on caeco-colonic motility by blocking the pathways by which CRF activates the motility, through a common mechanism involving a pertussis toxin-sensitive Gi protein.
Animals↗
CRF triggers the CNS release of TRH in stress-induced changes in gastric emptying.
Stress elicited by exposure to cold induces an increase of gastric emptying (GE) and intestinal transit of a caloric meal in mice and the release of corticotropin-releasing factor (CRF) and thyrotropin-releasing hormone (TRH) in the central nervous system (CNS). The present study proposed 1) to compare in mice the central effects of TRH, CRF, and cold-exposure stress on GE and intestinal transit of a caloric test meal consisting of 0.5 ml of reconstituted milk marked with 51Cr-labeled sodium chromate, and 2) using CRF and TRH antisera to determine whether TRH and CRF act in cascade or independently. The intracerebroventricular (icv) injection of TRH (0.5 microgram/kg) and CRF (1 microgram/kg), as well as cold stress, significantly increased GE, whereas 10-fold higher doses injected intraperitoneally were ineffective. The effect of cold stress on GE was abolished by prior icv injection of both CRF and TRH antisera. The effect of TRH was not blocked by CRF antiserum, but TRH antiserum suppressed the increase in GE induced by CRF. Moreover, both CRF and TRH antisera abolished changes in the rate of GE induced by exogenous CRF and TRH injection, respectively, therefore demonstrating the specific efficiency of immunoneutralization. CRF and cold stress both induced an increase in the rate of intestinal transit, while TRH had no effect. Antibodies to CRF prevented the intestinal stimulatory effect induced by CRF and cold stress. In contrast, antibodies to TRH were unable to antagonize either CRF or cold-stress induced increase in the rate of intestinal transit.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Neuropeptide Y and JO 1784, a selective sigma ligand, alter intestinal ion transport through a common, haloperidol-sensitive site.
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Animals↗
N-methyl-D-aspartate-induced neuronal activation is selectively modulated by sigma receptors.
The effects of two high-affinity sigma ligands, DTG (1,3-di(2-tolyl)guanidine) and haloperidol, on the activation of dorsal hippocampus pyramidal neurons induced by microiontophoretic application of N-methyl-D-aspartate (NMDA) were assessed electrophysiologically. Low doses of DTG (0.5-3 micrograms/kg i.v.) potentiated the NMDA response. This effect of DTG was blocked by haloperidol (10 micrograms/kg i.v.), but not by spiperone, a potent dopamine antagonist with low affinity for sigma receptors. These results suggest that sigma receptors modulate the NMDA-induced neuronal activation.
Animals↗
Selective stimulation of colonic motor response to a meal by sigma 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.
Animals↗
A comparison of the psychopharmacological profiles of phencyclidine, ketamine and (+) SKF 10,047 in the trimethyltin rat model.
The potential neuroprotective effects of phencyclidine, ketamine and (+) SKF 10,047 were investigated in the trimethyltin (TMT)-treated rat. Of the three drugs used in this study, only phencyclidine (5 mg/kg i.p.) reversed the behavioral hyperactivity and deficits in spatial localization of TMT-treated rats. Neurochemically, phencyclidine and (+) SKF 10,047 were without effect on the neurotransmitters (e.g. noradrenaline, dopamine, serotonin and 5-hydroxindole 3-acetic acid), examined in the amygdaloid cortex and hippocampal regions, while ketamine increased the steady state concentrations of 5-HIAA in the amygdaloid cortex. These results suggest the involvement of the phencyclidine receptor in reversal of the behavioural impairments produced by TMT in rats. The significance of these results with respect to phencyclidine and sigma receptors is discussed. The lack of effect of (+) SKF 10,047 in this model may reflect behavioural differences between phencyclidine and sigma ligands. It may be concluded that the TMT model can be exploited for studying the mechanism of action of molecules liable to have an effect at the phencyclidine receptor site, as opposed to the sigma receptor.
Animals↗