neuropeptide-y and igmesine

Recent evidence suggests that sigma receptor ligands and neuropeptide Y may act through the same pathways to modulate centrally mediated immune function. The present study demonstrated that both the sigma receptor ligand igmesine: (+)-N-cyclopropylmethy-N-methyl-1, 4-diphenyl-1-yl-but-3-en-1-ylamine, hydrochloride (JO 1784) (10(-7) and 10(-5) M) and neuropeptide Y (10(-9) and 10(-7) M) in vitro significantly reduced neutrophil phagocytosis and decreased mitogen stimulated lymphocyte proliferation. By contrast, central administration of JO 1784 (0.5 and 5 microg/5 microl) significantly reduced the activity of neutrophil phagocytosis, but enhanced lymphocyte proliferation without changing the serum concentration of corticosterone. Neuropeptide Y (10(-9) and 10(-7) M), following intracerebroventricular infusion, also decreased the neutrophil response, but significantly raised the corticosterone concentration. These results indicate that different mechanisms (involving various neurotransmitters and their receptors, changes in the activity of the hypothalamic-pituitary-adrenal axis, or sigma receptor subtypes) may be involved in the central effects of JO 1784 and neuropeptide Y.

Topics: Animals; Cinnamates; Corticosterone; Cyclopropanes; Immunity, Cellular; Indicators and Reagents; Injections, Intraventricular; Lymphocyte Activation; Male; Mitogens; Neuropeptide Y; Neutrophils; Phagocytosis; Rats; Rats, Sprague-Dawley; Receptors, sigma

In the CA3 region of rat dorsal hippocampus, several sigma ligands, such as 1,3-di(2-tolyl)guanidine (DTG), (+)-pentazocine and (+)-N-cyclopropylmethyl-N-methyl-1, 4-diphenyl-1-ethyl-but-3-en-1-ylamine hydrochloride (JO-1784), administered intravenously at low doses, potentiate selectively the pyramidal neuron firing activity induced by microiontophoretic applications of N-methyl-D-aspartate, without affecting those induced by quisqualate, kainate or acetylcholine. A similar potentiation of the N-methyl-D-aspartate response has also been found with microiontophoretic applications of neuropeptide Y, an effect exerted via delta receptors. The present experiments were carried out to determine the effects of these sigma ligands and of neuropeptide Y; in the CA1 and CA3 regions following unilateral destruction by a local injection of colchicine of the mossy fiber system, which is a major afference to CA3 pyramidal neurons. In the CA1 region, DTG, JO-1784 and neuropeptide Y did not potentiate the activation induced by microiontophoretic applications of N-methyl-D-aspartate. However, (+)-pentazocine potentiated the N-methyl-D-aspartate response, similarly to its effect in the CA3 region on the intact side. In the CA3 region, on the intact side, (+)-pentazocine, DTG, JO-1784 and neuropeptide Y induced a selective potentiation of N-methyl-D-aspartate-induced activation, in keeping with previous reports. On the lesioned side, the effect of (+)-pentazocine on the N-methyl-D-aspartate response was still present, but those of DTG, JO-1784 and neuropeptide Y were abolished. These results suggest that (+)-pentazocine, on the one hand, and DTG, JO-1784 and neuropeptide Y, on the other, are not acting on the same subtype of sigma receptors. Since (+)-pentazocine, JO-1784 and neuropeptide Y have been suggested to act on the sigma 1 subtype of receptors, these data suggest the existence of two subtypes of sigma 1 receptors. They also suggest that the receptors on which DTG, JO-1784 and neuropeptide Y are acting are located on the mossy fiber terminals in the CA3 region and are absent in the CA1 region.

Topics: Acetylcholine; Animals; Anticonvulsants; Cinnamates; Colchicine; Cyclopropanes; Electrophysiology; Guanidines; Hippocampus; Male; N-Methylaspartate; Nerve Fibers; Neuropeptide Y; Neurotoxins; Quisqualic Acid; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Receptors, sigma

1. The in vivo effects of the high affinity sigma ligands 1,3-di(2-tolyl)guanidine (DTG), (+)-N-cyclopropylmethyl-N-methyl-1,4-diphenyl-1- ethyl-but-3-en-1-ylamine hydrochloride (JO-1784), (+)-pentazocine and haloperidol, as well as of those of neuropeptide Y (NPY), on N-methyl-D-aspartate (NMDA)- and quisqualate (Quis)-induced neuronal activations of CA3 pyramidal neurones were assessed, using extracellular unitary recording, in control rats and in rats pretreated with a local injection of pertussis toxin (PTX), to evaluate the possible involvement of Gi/o proteins in mediating the potentiation of the neuronal response to NMDA by the activation of sigma receptors in the dorsal hippocampus. 2. Microiontophoretic applications as well as intravenous injections of (+)-pentazocine potentiated selectively the NMDA response in control rats as well as in PTX-pretreated animals. In contrast, the PTX pretreatment abolished the potentiation of the NMDA response by DTG, JO-1784 and NPY. Moreover, microiontophoretic applications of DTG induced a reduction of NMDA-induced neuronal activation. Neither in control nor in PTX-treated rats, did the sigma ligands and NPY have any effect on Quis-induced neuronal response. 3. In PTX-treated rats, the potentiation of the NMDA response induced by (+)-pentazocine was suppressed by haloperidol, whereas the reduction of the NMDA response by DTG was not affected by haloperidol. 4. This study provides the first in vivo functional evidence that sigma ligands and NPY modulate the NMDA response by acting on distinct receptors, differentiated by their PTX sensitivity.

Topics: Animals; Anticonvulsants; Cinnamates; Cyclopropanes; Drug Synergism; GTP-Binding Proteins; Guanidines; Haloperidol; Hippocampus; Ligands; Male; N-Methylaspartate; Neurons; Neuropeptide Y; Pentazocine; Pertussis Toxin; Pyramidal Cells; Quisqualic Acid; Rats; Rats, Sprague-Dawley; Receptors, sigma; Virulence Factors, Bordetella

The effects of putative sigma ligands and two neuropeptides on intestinal ion transport were evaluated in isolated sheets of whole mouse jejunum mounted in Ussing flux chambers. Serosal administration of neuropeptide Y (NPY), peptide YY (PYY), (+)-N-cyclopropylmethyl-N-methyl-1,4- diphenyl-1-ethyl-but-3-en-1-ylamine hydrochloride (JO 1784), di(ortho-tolyl)guanidine (DTG) and (+)- or (-)-N-allyl-normetazocine (NANM) produced concentration-related decreases in short-circuit current (Isc) without changes in tissue conductance. Although NPY and PYY were active in nanomolar concentrations, JO 1784, DTG and (+)- and (-)-NANM were active in micromolar concentrations; the rank order of potency in inhibiting Isc was PYY > NPY >> JO 1784 = (-)-N- cyclopropylmethyl-N-methyl-1,4-diphenyl-1-ethyl-but-3-en-1-ylamine hydrochloride > DTG > (+)-NANM = (-)-NANM. Serosal application of tetrodotoxin effectively blocked the decrease in Isc associated with all of the ligands tested. The activity of the serosally applied ligands was blocked by prior application of chlorisondamine, a ganglionic blocker. The effects of JO 1784 and NPY were evaluated using antagonists of several receptor types. Although application of serosal haloperidol had no effect alone up to concentrations of 1 microM, this compound produced a rightward displacement in both the NPY and JO 1784 concentration-effect curves. In contrast, sulpiride, SCH-23390, naloxone, yohimbine and prazosin failed to antagonize the effects of NPY or JO 1784.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Cinnamates; Cyclopropanes; Guanidines; In Vitro Techniques; Ion Transport; Jejunum; Male; Mice; Mice, Inbred ICR; Neuropeptide Y; Peptide YY; Peptides; Phenazocine; Receptors, sigma

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

In an in vivo electrophysiological paradigm, we have shown in the companion paper that neuropeptide Y (NPY) potentiates N-methyl-D-aspartate (NMDA)-induced neuronal activation via a non-Y1, non-Y2, non-Y3 receptor subtype, in the rat CA3 dorsal hippocampus. Because sigma ligands have also been shown to potentiate NMDA-induced activation and because NPY and peptide YY have been reported to have high affinity for sigma binding sites, the present study was carried out to assess the possibility that the modulation of the NMDA response by NPY might be mediated by a sigma receptor. In the same electrophysiological paradigm, low doses of haloperidol and alpha-(4-fluorophenyl)-4-(5-fluoro-2- pyrimidinyl)-1-piperazine butanol, two antagonists of sigma receptors, reversed the potentiation of the NMDA response induced by NPY, [Leu31, Pro34]NPY or NPY13-36 and blocked the suppressant effect of desamido-NPY on the NMDA response. In contrast, spiperone, which has low affinity for sigma sites, was ineffective in suppressing NPY, as well as desamido-NPY-induced modulation of the NMDA response. In our model, peptide YY, which acts as a NPY antagonist by suppressing the potentiation of the NMDA response induced by NPY, also antagonized the potentiation of the NMDA response induced by the administration of low doses of di(2-tolyl)guanidine and (+)N-cyclopropyl-methyl-N-,methyl-1,4- diphenyl-1-ethyl-but-3-en-1-ylamine hydrochloride, two high-affinity sigma agonists.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Cinnamates; Cyclopropanes; Drug Synergism; Guanidines; Haloperidol; Hippocampus; Male; N-Methylaspartate; Neuropeptide Y; Pyrimidines; Rats; Rats, Sprague-Dawley; Receptors, Neuropeptide Y; Receptors, sigma; Spiperone

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

Topics: Animals; Bombesin; Cinnamates; Cisterna Magna; Corticotropin-Releasing Hormone; Cyclopropanes; Dose-Response Relationship, Drug; Gastric Acid; Humans; Interleukin-1; Male; Microinjections; Neuropeptide Y; Paraventricular Hypothalamic Nucleus; Pentagastrin; Psychotropic Drugs; Pyrimidines; Rats; Rats, Sprague-Dawley

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.

Topics: Animals; Cinnamates; Colon; Corticotropin-Releasing Hormone; Cyclopropanes; Gastrointestinal Motility; GTP-Binding Proteins; Injections, Intraventricular; Male; Neuropeptide Y; Pertussis Toxin; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, sigma; Stress, Psychological; Virulence Factors, Bordetella

Topics: Animals; Cinnamates; Cyclopropanes; Haloperidol; In Vitro Techniques; Intestinal Mucosa; Intestines; Ion Channels; Male; Mice; Mice, Inbred ICR; N-Methylaspartate; Neuropeptide Y; Receptors, Opioid; Receptors, Opioid, delta