High intensity social conflict in the Swiss albino mouse induces analgesia modulated by 5-HT1A receptors

Social conflict between mice produces analgesia in the attacked mouse. Both the magnitude and type (opioid or nonopioid) of this analgesia have been related to attack intensity and strain of mouse. In the present study low intensity social conflict (7 bites) did not produce analgesia, whereas high intensity - 30 and 60 bites interactions produced, respectively, short-lasting (5 min) and very short-lasting (1 min) analgesia in Swiss albino mice, when compared with nonaggressive interaction (0 bite). The 30 bites aggressive interaction induced analgesia (AIIA) was not affected by IP injection of either naloxone (5.0 and 7.5 mg/kg) or diazepam (0.5, 1.0, 2.0 and 4.0 mg/kg). However, this attack-induced analgesia was reduced after IP administration of the 5-HT1A agonists, gepirone (0.3 and 3.0 mg/kg) and BAY R 1531 (0.01 mg/kg). These results indicate that the analgesia induced by 30 bites social conflict in Swiss albino mice does not involve opioid and GABA-benzodiazepine (GABA-BZD) mechanisms. In addition, they suggest that high-intensity social conflict activates serotonergic pain modulatory systems that act through 5-HT1A receptors. Copyright (C) 1997 Elsevier B.V.

Molecular orbital calculation for the model compounds of kainoid amino acids, agonists of excitatory amino acid receptors. Does the kainoid C4-substituent directly interact with the receptors?

Kainoid amino acids are agonists of the AMPA/kainate receptors and exhibit highly potent neuroexcitatory activity. From the results of extensive structure-activity relationship studies, we previously postulated that the C4-substituent of the kainoid amino acids interacts with an allosteric site of the glutamate receptor with electron-donating character. In order to investigate the mode of action in more detail, molecular orbital calculation for model compounds of the kainoid were performed. The results indicated that the HOMO energy level of the C4-substituent is involved in the potent neuroexcitatory activity, thus supporting our hypothesis. (C) 2002 Elsevier B.V. Ltd. All rights reserved.

Triiodothyronine mimics the effects of estrogen in breast cancer cell lines

MCF-7 (estrogen receptor positive - ER(+)) and MDA-MB-231 (estrogen receptor negative - ER(-)) are human breast cancer cell lines which express functional thyroid hormone receptors (c-erb A alpha 1 and c-erb beta 1) as indicated by stimulation of mitochondrial alpha-glycerophosphate dehydrogenase. In MCF-7, mimicking E(2), T-3 stimulated growth in a dose-dependent (10(10) M-10(-8) M) manner, induced the expression of progesterone receptor and growth factor TGF alpha mRNAs and inhibited that of TGF beta mRNA; T-3 also increased progesterone binding and LDH5 isozyme activities. None of these effects were observed in (ER(-)) MDA-MB-231 cells. 10(-6) M tamoxifen (TAM) reverted growth stimulation, suppressed progesterone receptor and TGF alpha mRNA induction and restored TGF beta mRNA to control levels in T-3-treated MCF-7 cells. That T-3 is acting in MCF-7 cells via its binding to ER is suggested by the immunoprecipitation of pre-bound I-125-T-3 from MCF-7 nuclear extracts by an ER-specific monoclonal antibody and by the displacement of H-3-estradiol binding to ER by radioinert T-3. Copyright (C) 1996 Elsevier B.V. Ltd.

Nitric oxide and anglotensin II receptors mediate the pressor effect of angiotensin II: A study in conscious and zoletil-anesthetized rats

The circumventricular structures of the central nervous system and nitric oxide are involved in arterial blood pressure control, and general anesthesia may stimulate the central renin-angiotensin system. We therefore investigated the central role of angiotensin 11 and nitric oxide on the regulation of systemic arterial blood pressure in conscious and anesthetized rats. METHODS: Rats with stainless steel cannulae implanted into their lateral ventricle were studied. We injected the AT(1) and AT(2) angiotensin 11 receptor antagonists, losartan and PD123319, L-NAME, 7-nitroindazole (nitric oxide synthetase inhibitors), and FK409 (nitric oxide donor agent) into the lateral ventricles. Mean arterial blood pressure (MAP) was recorded in conscious and zoletil-anesthetized rats. RESULTS: Mean +/- (SEM) baseline MAP was 117.5 +/- 2 mm Hg. Angiotensin II injected into the brain lateral ventricle increased MAP from 136.5 +/- 2 min Hg to 138.5 +/- 4 mm Hg (Delta 16 +/- 3 mm Hg to Delta 21 +/- 3 mm Hg) for all experimental groups versus control from 116 +/- 2 mm Hg to 120 +/- 3 mm Hg (Delta 3 +/- 1 mm Hg to A5 +/- 2 mm Hg) (P < 0.05). L-NAME or 7-nitroindazole enhanced the angiotensin II pressor effect (P < 0.05). Prior injection of losartan and PD123319 decreased the angiotensin 11 pressor effect and the enhancement effect of L-NAME and 7-nitroindazole (P < 0.05). Zoletil anesthesia did not interfere with the effects of angiotensin 11, AT,, AT2 antagonists, or nitric oxide synthetase inhibitors. CONCLUSIONS: Endogenous nitric oxide functions tonically as a central inhibitory modulator of the angiotensinergic system. AT, and AT2 receptors influence the angiotensin 11 central control of arterial blood pressure. Zoletil anesthesia did not interfere with these effects. (Anesth Analg 2007;105:1293-7)

Cellular recruitment and cytokine generation in a rat model of allergic lung inflammation are differentially modulated by progesterone and estradiol

We evaluated the role of estradiol and progesterone in allergic lung inflammation. Rats were ovariectomized (Ovx) and, 7 days later, were sensitized with ovalbumin (OA) and challenged after 2 wk with inhaled OA; experiments were performed 1 day thereafter. Ovx-allergic rats showed reduced cell recruitment into the bronchoalveolar lavage (BAL) fluid relative to sham-Ovx allergic rats, as was observed in intact allergic rats treated with ICI-182,780. Estradiol increased the number of cells in the BAL of Ovx-allergic rats, whereas progesterone induced an additional reduction. Cells of BAL and bone marrow (BM) of Ovx-allergic rats released elevated amounts of IL-10 and reduced IL-1 beta and TNF-alpha. BM cells of Ovx-allergic rats released increased amounts of IL-10 and lower amounts of IL-4. Estradiol treatment of Ovx-allergic rats decreased the release of IL-10 but increased that of IL-4 by BM cells. Estradiol also caused an increased release of IL-1 beta and TNF-alpha by BAL cells. Progesterone significantly increased the release of IL-10, IL-1 beta, and TNF-alpha by BAL cells and augmented that of IL-4 by BM cells. Degranulation of bronchial mast cells from Ovx rats was reduced after in vitro challenge, an effect reverted by estradiol but not by progesterone. We suggest that the serum estradiol-to-progesterone ratio might drive cellular recruitment, modulating the pulmonary allergy and profile of release of anti-inflammatory or inflammatory cytokines. The existence of such dual hormonal effects suggests that the hormone therapy of asthmatic postmenopausal women and of those suffering of premenstrual asthma should take into account the possibility of worsening the pulmonary conditions.

The antiepileptic activity of JSTX-3 is mediated by N-methyl-D-aspartate receptors in human hippocampal neurons

We analyzed the effect of the acylpolyaminetoxin JSTX-3 on the epileptogenic discharges induced by perfusion of human hippocampal slices with artificial cerebrospinal fluid lacking Mg2+ or N-methyl-D-aspartate. Hippocampi were surgically removed from patients with refractory medial temporal lobe epilepsy, sliced in the surgical room and taken to the laboratory immersed in normal artificial cerebrospinal fluid. Epileptiform activity was induced by perfusion with Mg2+-free artificial cerebrospinal fluid or by iontophoretically applied N-methyl-D-aspartate and intracellular and field recordings of CAI neurons were performed. The ictal-like discharges induced by Mg2+-free artificial cerebrospinal fluid and N-methyl-D-aspartate were blocked by incubation with JSTX-3. This effect was similar to that obtained with the N-methyl-D-aspartate receptor antagonist DL(-)2-amino-5 phosphonovaleric acid. Our findings suggest that in human hippocampal neurons, the antiepileptic effect of JSTX-3 is mediated by its action on N-methyl-D-aspartate receptor.

Modulation of intercellular communication in macrophages: possible interactions between GAP junctions and P2 receptors

Gap junctions are connexin-formed channels that play an important role in intercellular communication in most cell types. In the immune system, specifically in macrophages, the expression of connexins and the establishment of functional gap junctions are still controversial issues. Macrophages express P2X(7) receptors that, once activated by the binding of extracellular ATP, lead to the opening of transmembrane pores permeable to molecules of up to 900 Da. There is evidence suggesting an interplay between gap junctions and P2 receptors in different cell systems. Thus, we used ATP-sensitive and -insensitive J774.G8 macrophage cell lines to investigate this interplay. To study junctional communication in J774-macrophage-like cells, we assessed cell-to-cell communication by microinjecting Lucifer Yellow. Confluent cultures of ATP-sensitive J774 cells (ATP-s cells) are coupled, whereas ATP-insensitive J774 cells (ATP-i cells), derived by overexposing J774 cells to extracellular ATP until they do not display the phenomenon of ATP-induced permeabilization, are essentially uncoupled. Western-blot and reverse-transcription polymerase chain reaction assays revealed that ATP-s and ATP-i cells express connexin43 (Cx43), whereas only ATP-s cells express the P2X(7) receptor. Accordingly, ATP-i cells did not display any detectable ATP-induced current under whole-cell patch-clamp recordings. Using immunofluorescence microscopy, Cx43 reactivity was found at the cell surface and in regions of cell-cell contact of ATP-s cells, whereas, in ATP-i cells, Cx43 immunoreactivity was only present in cytosolic compartments. Using confocal microscopy, it is shown here that, in ATP-s cells as well as in peritoneal macrophages, Cx43 and P2X(7) receptors are co-localized to the membrane of ATP-s cells and peritoneal macrophages.

Forebrain angiotensin type 1 receptors and parabrachial serotonin in the control of NaCl and water intake

This study investigated the roles of serotonin (5-HT) receptors in the lateral parabrachial nucleus (LPBN), and brain angiotensin type 1 (AT(1)) receptors in the intake of 0.3 M NaCl and water induced by angiotensin II (ANG II). Rats were implanted with stainless steel cannulas for injections into tho subfornical organ (SFO) and into the LPBN. Bilateral LPBN pretreatment with the nonselective serotonergic 5-HT1/5-HT2 receptor antagonist methysergide (4 mu g/200 nl) markedly enhanced 0.3 M NaCl intake induced by injections of ANG II (20 ng/200 nl) into the SFO. Pretreatment of the SFO with the AT(1) receptor antagonist losartan (1 mu g/200 nl) blocked the intake of 0.3 M NaCl induced by ANG II in combination with LPBN methysergide injections. These results suggest that serotonergic mechanisms associated with the LPBN inhibit the expression of salt appetite induced by ANG II injections into Ihs SFO. In addition, the results indicate that the enhanced NaCl intake generated by central administration of ANG II in the presence of LPBN 5-HT blockade is mediated bg brain ATI receptors.