Higher environmental temperature-induced increase in body temperature: Involvement of serotonin in GABA mediated interaction of opioidergic system

Exposure (2 h) of adult male albino rats to higher environmental temperature (HET, 40°C) significantly increased body temperature (BT). Administration of (a) 5-HTP (5 mg/kg, i.p.) or morphine (1 mg/kg, i.p.) or physostigmine (0.2 mg/kg, i.p.) alone significantly increased and (b) methysergide (1 mg/kg, i.p.) or naloxone (1 mg/kg, i.p.) or atropine (5 mg/kg, i.p.) reduced the BT of both normal and HET exposed rats. Further, it was observed that morphine prevented the methysergide-induced hypothermia and 5-HTP potentiated the morphine-induced hyperthermia in both normal and HET exposed conditions. Biochemical study also indicates that serotonin metabolism was increased but GABA utilization was reduced following exposure to HET. 5-HTP or bicuculline-induced hyperthermia in control and HET exposed rat was potentiated with the coadministration of bicuculline and 5-HTP. The cotreatment of bicuculline with methysergide prevented the methysergide-induced attenuation of BT of heat exposed rat, rather BT was significantly enhanced indicating that inhibition of GABA system under heat exposed condition may activate the serotonergic activity. Further (a) enhancement of (i) morphine-induced hyperthermia with physostigmine (ii) physostigmine- or morphine + physostigmine-induced increase of BT with 5-HTP and (b) reduction of (i) morphine- or morphine + 5-HTP-induced hyperthermia with atropine and (ii) atropine-induced hypothermia with 5-HTP in both normal and HET exposed conditions suggest that HET exposure activates the cholinergic system through the activation of opioidergic and serotonergic system and hence increased the BT. Thus, it may be concluded that there is an involvement of serotonergic regulation in the opioidergic-cholinergic interaction via GABA system in HET-induced increase in BT.     

Increased antidepressant-like effect of desipramine combined with central stimulants (caffeine and amphetamine) in mice

Desipramine is a widely used antidepressive agent that inhibits the reuptake of noradrenaline and serotonin, and central stimulants such as caffeine and amphetamine help to release noradrenaline and serotonin. This work aimed to evaluate whether the combination of these agents could produce a stronger antidepressant-like effect than either of the drugs alone. To this end, male mice were treated with different doses of desipramine, caffeine, amphetamine, desipramine-caffeine and desipramine-amphetamine. The results showed that all drugs produced decreased immobility time in the forced swimming model. The combined treatment of desipramine (0.31, 1.0 or 3.1 mg/kg i.p.) with caffeine or amphetamine (0.31 or 1 mg/kg i.p.) reduced immobility time greater than either of those drugs alone. The combined treatment of desipramine (0.31, 1 and 3.1 mg/kg i.p.) with amphetamine or caffeine (0.1 and 1 mg/kg i.p.) did not increase the motor activity significantly compared to the control. These results also suggested that drugs which promote the release of noradrenaline and serotonin could increase antidepressant-like effect of desipramine.     

LSD and related drugs as DA antagonists: Receptor-mediated effects on the synthesis and turnover of DA

We have earlier shown that d-lysergic acid diethylamide, LSD and its 2-bromo derivative, BOL like the dopamine (DA) antagonists haloperidol increased the rate of the $\text{in vivo}$ tyrosine hydroxylation in the striatum measured as the accumulation of DOPA after decarboxylase inhibition.Now we have found that several agents structurally similar to LSD increase the $\text{in vivo}$ tyrosine hydroxylation in the striatum. Psilocybin (50 mg/kg i.p.) and N,N-dimethyltryptamine (50 mg/kg i.p.) caused a short-lasting increase of DOPA accumulation, while mescaline (10 – 100 mg/kg i.p.) did not increase the DOPA accumulation. A marked increase of DOPA accumulation was observed after the 5-hydroxytryptamine (5-HT) antagonist cyproheptadine. The effects of LSD and structurally related drugs on the DOPA accumulation in the striatum appear to be mediated via DA antagonism at receptor level. However, these agents may control the DOPA accumulation via other receptors than DA receptors e.g. 5-HT receptors. A control of DOPA accumulation via receptors other than DA receptors appears to be predominant after treatment with N,N-dimethyltryptamine or psilocybin.     

Caffeine-induced locomotor activity: Possible involvement of GABAergic-dopaminergic-adenosinergic interaction

Caffeine (10–40 mg/kg, p.o.) enhanced locomotor activity (LA). Administration of GABA antagonist, bicuculline (0.5–1.0 mg/kg, i.p.), potentiated this caffeine-induced increase of LA, as well as LA of control rats. Treatment with the GABA agonist, muscimol (0.25–1 mg/kg, i.p.) or dopaminergic antagonist, haloperidol (0.25–1 mg/kg, i.p.) or muscarinic receptor blocker, atropine (3.75–5 mg/kg, i.p.), or inhibitor of acetylcholine esterase physostigmine (0.05–0.30 mg/kg, i.p.) or nicotine (0.5–1.5 mg/kg, i.p.) an nicotinic receptor agonist all decreased the LA of both caffeinetreated and control rats. Haloperidol-induced reduction in caffeine-induced increase in LA was found to be withdrawn with higher dose of caffeine. The dopamine agonist L-Dopa (75–150 mg/kg, p.o.) along with carbidopa (10 mg/kg, p.o.) increased the LA in control rats and potentiated the LA of caffeine treated rats. The haloperidol attenuated the bicuculline-induced increase in LA and atropine or physostigmine attenuated the bicuculline or L-Dopa+carbidopa-induced increase in LA in both caffeine treated and control rats when those drugs were administered concomitantly with bicuculline or L-Dopa+carbidopa. These results suggest that (a) the GABAergic system has direct role in the regulation of LA, and (b) caffeine potentiates LA by antagonism of the adenosine receptor and activation of the dopaminergic system which, in turn, reduces GABAergic activity through the reduction of cholinergic system.     

Effect of repeated treatment with desipramine in the behavioral "despair" test in rats: antagonism by "atypical" but not "classical" neuroleptics or antiadrenergic drugs

A 7-day treatment with 20 mg/kg/day desipramine reduced the immobility time in the behavioral "despair" test in rats. The effect of DMI was antagonized by sulpiride (100 mg/kg i.p.), metoclopramide (20 mg/kg i.p.) and clopazine (20 mg/kg i.p.) but not by haloperidol (0.5 mg/kg i.p.) or chlorpromazine (5 mg/kg i.p.). Alpha-adrenoreceptor blockers (prazosin 3 mg/kg s.c.; aceperone 10 mg/kg i.p.; azapetine 24 mg/kg s.c.; phentolamine 20 mg/kg i.p.), dl-propranolol (5 mg/kg i.p.) and clonidine (0.1 mg/kg i.p.) failed to modify the anti-immobility effect of DMI. The data suggest that a particular subtype of dopamine receptors is involved in the anti-immobility effect of a 7-day treatment with DMI in the behavioral "despair" test in rats.     

Effects of the Histamine H3-Agonist (R)-α-Methylhistamine and the Antagonist Thioperamide on Histamine Metabolism in the Mouse and Rat Brain

To study the feedback control by histamine (HA) H3-receptors on the synthesis and release of HA at nerve endings in the brain, the effects of a potent and selective H3-agonist, (R)-alpha-methylhistamine, and an H3-antagonist, thioperamide, on the pargyline-induced accumulation of tele-methylhistamine (t-MH) in the brain of mice and rats were examined in vivo. (R)-alpha-Methylhistamine dihydrochloride (6.3 mg free base/kg, i.p.) and thioperamide (2 mg/kg, i.p.), respectively, significantly decreased and increased the steady-state t-MH level in the mouse brain, whereas these compounds produced no significant changes in the HA level. When administered to mice immediately after pargyline (65 mg/kg, i.p.), (R)-alpha-methylhistamine (3.2 mg/kg, i.p.) inhibited the pargyline-induced increase in the t-MH level almost completely during the first 2 h after treatment. Thioperamide (2 mg/kg, i.p.) enhanced the pargyline-induced t-MH accumulation by approximately 70% 1 and 2 h after treatment. Lower doses of (R)-alpha-methylhistamine (1.3 mg/kg) and thioperamide (1 mg/kg) induced significant changes in the pargyline-induced t-MH accumulation in the mouse brain. In the rat, (R)-alpha-methylhistamine (3.2 mg/kg, i.p.) and thioperamide (2 mg/kg, i.p.) also affected the pargyline-induced t-MH accumulation in eight brain regions and the effects were especially marked in the cerebral cortex and amygdala. These results indicate that these compounds have potent effects on HA turnover in vivo in the brain.     

A behavioural study of the effect of pentadecapeptide BPC 157 in Parkinson's disease models in mice and gastric lesions induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydrophyridine.

The effect of a stomach pentadecapeptide, BPC 157, on Parkinson's disease in mice was investigated, along with its salutary activity on stomach lesions induced by parkinsongenic agents. Parkinsongenic agents, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (30.0 mg x kg(-1)b.w. i.p. once daily for 6d, and after 4d once 50.0 mg x kg(-1)b.w. i.p.) or reserpine (5.0 mg x kg(-1)b.w. i.p.) were applied i.p. BPC 157 (1.50 microg or 15.0 ng x kg(-1)b.w. i.p.) was applied 15 min before or alternatively 15 min after each MPTP administration. In reserpine studies, BPC 157 (10.0 microg or 10.0 ng x kg(-1)b.w. i.p.) was given either 15 min before reserpine or in the already established complete catalepsy 24 h thereafter. BPC 157 strongly improved the MPTP-impaired somatosensory orientation and reduced the MPTP-induced hyperactivity, and most importantly, MPTP-motor abnormalities (tremor, akinesia, catalepsy -otherwise very prominent in saline control), leading to almost complete abolition of otherwise regularly lethal course of MPTP treatment in controls. Likewise, in reserpine experiments, BPC 157 strongly prevented the development of otherwise very prominent catalepsy and when applied 24 h thereafter reversed the established catalepsy. In addition, a reduction of reserpine-hypothermy (BPC 157 pre-treatment) and reversal of further prominent temperature fall (BPC 157 post-treatment) have been consistently observed. Taking together these data, as the two most suitable animal models were consistently used and since the high effectiveness was demonstrated in pre- and post-treatment, microg and ng regimens, BPC 157 as an organoprotector should be further therapeutically investigated. Additionally, given in either regimen, pentadecapeptide BPC 157 strongly attenuated the stomach lesions in mice that otherwise consistently appeared in mice treated with the parkinsogenic neurotoxin MPTP.     

Histaminergic Modulation of Hippocampal Acetylcholine Release In Vivo

Abstract: In order to elucidate the modulatory role of the histaminergic neural system in the cholinergic neural system, the acetylcholine release from the CA1-CA3 region in the hippocampus of anesthetized rats was studied by an in vivo microdialysis method coupled with HPLC-electrochemical detection. The mean value for the basal acetylcholine release was 0.98 β 0.04 pmol/20 min. The acetylcholine release was increased to 172% of the basal level when an electrical stimulation at 200 μA was applied to the tuberomammillary nucleus. An administration of α-fluoromethylhistidine (100 mg/kg i.p.) blocked the electrically evoked release of histamine both from the septal-diagonal band complex and the hippocampus, and abolished the electrically evoked release of acetylcholine from the hippocampus. Zolantidine (5 mg/kg i.p.) attenuated the increase in the electrically stimulated acetylcholine release, but pyrilamine (5 mg/kg i.p.) did not attenuate the increase in the acetylcholine release. These drugs showed no significant effect on the basal acetylcholine release. An administration of ( R )-α-methylhistamine (5 mg/kg i.p.) caused a decrease in the acetylcholine release to 48.7% of the basal level, whereas thioperamide (5 mg/kg i.p.) caused an increase in the acetylcholine release 60 min after the injection. These results suggest that the histaminergic system may contribute to the modulation of the activity of the septohippocampal cholinergic system, mainly through H₂ receptprs.     

Antibiotic treatment with ampicillin accelerates the healing of colonic damage impaired by aspirin and coxib in the experimental colitis. Importance of intestinal bacteria, colonic microcirculation and proinflammatory cytokines

Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used for their anti-inflammatory, analgesic and antipyretic effects, however their use is associated with the broad spectrum of side effects observed in human as well as the experimental animals. Despite damaging activity of NSAIDs in upper gastrointestinal (GI) tract, these drugs exert deleterious influence in lower GI tract, including colon. The role of GI microflora in the pathogenesis of NSAIDs-induced experimental colonic damage is not completely understood. The aim of this study was 1) to evaluate the relative importance of the GI microflora on the experimental colonic damage in the presence of caused by NSAID, and 2) to assess the efficacy of antibiotic treatment with ampicillin on the process of healing of colitis. We compared the effect of vehicle, ASA applied 40 mg/kg intragastrically (i.g.) or the selective cyclooxygenase (COX)-2 inhibitor, celecoxib (25 mg/kg i.g.) without or with ampicillin treatment (800 mg/kg i.g.) administered throughout the period of 10 days, on the intensity of TNBS-induced colitis in rats. The severity of colonic damage, the alterations in the colonic blood flow (CBF) and myeloperoxidase (MPO) activity, the mucosal expression of TNF-α, IL-1β, COX-2, VEGF and iNOS and the plasma concentration of TNF-α and IL-1β were assessed. In all rats, the faeces samples as well as those from the colonic mucosa, blood, liver and spleen underwent microbiological evaluation for intestinal bacterial species including Escherichia coli and Enterococcus spp. The administration of TNBS resulted in macroscopic and microscopic lesions accompanied by the significant fall in the CBF, an increase in tissue weight and 4-5-fold rise in the MPO activity and a significant increase in the plasma IL-1β and TNF-α levels. ASA or celecoxib significantly increased the area of colonic lesions, enhanced MPO activity and caused the marked increase in colonic tissue weight and plasma IL-1β and TNF-α levels, as well as an overexpression of mRNA for IL-1β and TNF-α, COX-2, VEGF and iNOS in the colonic tissue. ASA and coxib also resulted also in a significant increase of E. coli counts in the stool at day 3 and day 10 day of the observation compared with the intact rats. Moreover, E. coli translocation from the colon to the blood and extraintestinal organs such as liver and spleen in the group of rats treated without or with ASA and coxib. E. coli was the most common bacteria isolated from these organs. Treatment with ampicillin significantly attenuated the ASA- or celecoxib-induced increase in plasma levels of IL-1β and TNF-α and suppressed the mucosal mRNA expression for IL-1β and TNF-β, COX-2, iNOS and VEGF in the colonic mucosa. Ampicillin administration caused a significant fall in the number of E. coli in the faeces at day 3 and day 10 of observation in ASA- and coxib-treated rats with colitis. Antibiotic therapy markedly reduced bacterial translocation to the colonic tissue and the extraintestinal organs such as the liver and spleen. We conclude that administration of ASA and to lesser extent of celecoxib, delays the healing of experimental colitis and enhances the alterations in colonic blood flow, proinflammatory markers such as IL-1β, TNF-α, COX-2, iNOS and VEGF and increased intestinal mucosal permeability resulting in the intestinal bacterial translocation to the blood, spleen and liver. Antibiotic treatment with ampicillin is effective in the diminishing of the severity of colonic damage, counteracts both the NSAID-induced fall in colonic microcirculation and bacterial E.coli translocation to the extraintestinal organs.     

Effects of phenobarbital and sodium salicylate on cytochrome P-450 mixed function oxygenase and glutathione S-transferase activities in rat brain

The effects of acute and therapeutic doses of phenobarbital and sodium salicylate on cytochrome P-450 mixed function oxygenase (EC 1.14.14.1) and glutathione S-transferase (EC 2.5.1.18) activities have been studied in rat brain and compared with those of rat liver. P-450 enzymic activity was assayed by N-demethylation of p-chloro-N-methylaniline and 1-chloro-2,4-dinitrobenzene was used as substrate for glutathione S-transferase activity. The acute effects of a single daily dose of phenobarbital (75 mg/kg/day;i.p.) and sodium salicylate (500 mg/kg/day;i.p.) for 3 days increased cytochrome P-450 as well as glutathione S-transferase in rat liver. But the same doses of both drugs decreased glutathione S-transferase levels in rat brain and increased cytochrome P-450 dependent N-demethylation of p-chloro-N-methylaniline. The therapeutic doses of sodium salicylate (50 mg/kg/day;i.p.) and phenobarbital (10 mg/kg/day;i.p.) daily for 21 days increased cytochrome P-450 in rat liver as well as in brain. The increase in brain glutathione S-transferase by prolonged treatment of phenobarbital was significant compared to the control values.     

Prevention of kainic acid-induced changes in nitric oxide level and neuronal cell damage in the rat hippocampus by manganese complexes of curcumin and diacetylcurcumin

Curcumin is a natural antioxidant isolated from the medicinal plant Curcuma longa Linn. We previously reported that manganese complexes of curcumin (Cp-Mn) and diacetylcurcumin (DiAc-Cp-Mn) exhibited potent superoxide dismutase (SOD)-like activity in an in vitro assay. Nitric oxide (NO) is a free radial playing a multifaceted role in the brain and its excessive production is known to induce neurotoxicity. Here, we examined the in vivo effect of Cp-Mn and DiAc-Cp-Mn on NO levels enhanced by kainic acid (KA) and L-arginine (L-Arg) in the hippocampi of awake rats using a microdialysis technique. Injection of KA (10 mg/kg, i.p.) and L-Arg (1000 mg/kg, i.p.) significantly increased the concentration of NO and Cp-Mn and DiAc-Cp-Mn (50 mg/kg, i.p.) significantly reversed the effects of KA and L-Arg without affecting the basal NO concentration. Following KA-induced seizures, severe neuronal cell damage was observed in the CA1 and CA3 subfields of hippocampal 3 days after KA administration. Pretreatment with Cp-Mn and DiAc-Cp-Mn (50 mg/kg, i.p.) significantly attenuated KA-induced neuronal cell death in both CA1 and CA3 regions of rat hippocampus compared with vehicle control, and Cp-Mn and DiAc-Cp-Mn showed more potent neuroprotective effect than their parent compounds, curcumin and diacetylcurcumin. These results suggest that Cp-Mn and DiAc-Cp-Mn protect against KA-induced neuronal cell death by suppression of KA-induced increase in NO levels probably by their NO scavenging activity and antioxidative activity. Cp-Mn and DiAc-Cp-Mn have an advantage to be neuroprotective agents in the treatment of acute brain pathologies associated with NO-induced neurotoxicity and oxidative stress-induced neuronal damage such as epilepsy, stroke and traumatic brain injury.     

A new simple mouse model for the in vivo evaluation of cholecystokinin (CCK) antagonists: comparative potencies and durations of action of nonpeptide antagonists

A new simple mouse assay for the in vivo evaluation of CCK antagonists which is based upon visual determination of the gastric emptying of a charcoal meal is described. CCK-8 (24 micrograms/kg s.c.) but not various other peptide and nonpeptide agents effectively inhibited gastric emptying in this test system. The effect of CCK-8 was antagonized by established peripheral CCK antagonists but not representative agents of various other pharmacological classes. The rank order of potency of the CCK antagonists were: L-364,718 (ED50 = 0.01 mg/kg, i.v.; 0.04 mg/kg, p.o.) greater than Compound 16 (ED50 = 1.5 mg/kg, i.v.; 2.0 mg/kg p.o.) greater than asperlicin (ED50 = 14.8 mg/kg i.v.) greater than proglumide (ED50 = 184 mg/kg i.v.; 890 mg/kg, p.o.). Duration of action studies based upon ED50 values determined at various time intervals after oral administration showed that L-364,718 and proglumide are considerably longer acting than Compound 16. Asperlicin (ED50 greater than 300 mg/kg, p.o.) was ineffective as a CCK antagonist when administered orally. These data provide the first direct comparisons of the in vivo potencies of current CCK antagonists and demonstrate the utility of a new simple mouse assay for the in vivo characterization of peripheral CCK antagonists.     

Inhibition of mitomycin C-induced sister-chromatid exchanges in mouse bone marrow cells by the immunopotentiators Krestin and Lentinan

We have carried out an investigation to determine whether or not the sister-chromatid exchange frequencies (SCEs) observed in bone marrow cells in mice treated with mitomycin C (MMC) are inhibited by the immunopotentiators Krestin and Lentinan. We found that mitomycin C (2 mg/kg, i.v.)-induced SCEs were inhibited in 27% of the mice treated with Krestin (300 mg/kg, i.p.) and in 23% of the mice treated with Lentinan (1 mg/kg, i.p.). The effects of Krestin were found to be dose-dependent in inhibition of MMC-induced SCEs while those of Lentinan were not. Our findings therefore suggest that Krestin and Lentinan are not only useful for cancer treatment as immunopotentiators in combination with anticancer drugs but may also prevent the increase of chromosomal damage induced by anticancer drugs.     

Effect of pentylenetetrazol on the carbaryl-induced changes of serotonin metabolism in rat-brain hypothalamus

Carbaryl (200 mg/kg or 400 mg/kg, p.o.) significantly elevated serotonin (5-HT) (57–109%) and 5-hydroxy-indoleacetic acid (5-HIAA) (60–78%) levels at 1.0 h in the hypothalamic region of adult male rat brain. Further, administration of carbaryl (200 mg/kg, p.o.) for different time intervals (0.5 h, 1.0 h, and 2.0 h) revealed that both 5-HT and 5-HIAA levels elevated maximally at 0.5 h in hypothalamus. These regional 5-HT and 5-HIAA levels were not significantly affected with pentylenetetrazol (PTZ) at any time after its treatment. But simultaneous administration of carbaryl (200 mg/kg, p.o.) and PTZ (60 mg/kg, s.c.) reduced the carbaryl-induced elevation of both 5-HT and 5-HIAA leveis. Measurement of (i) probenecid-induced (200 mg/kg, i.p.) accumulation and (ii) pargyline-induced (75 mg/kg, i.p.) depletion of hypothalamic 5-HIAA level in the absence or presence of carbaryl (200 mg/kg, p.o.) and/or PTZ (60 mg/kg, s.c.) revealed that (a) carbaryl enhanced the synthesis as well as the breakdown of 5-HT, (b) PTZ had no effect on either of these processes of 5-HT, and (c) carbaryl-induced increased catabolism of 5-HT became normal in the presence of PTZ.     

Protection of mice from malaria after co-administration of recombinant mouse granulocyte-macrophage colony- stimulating factor and methionine-enkephalin

The protective effect of co-administration of recombinant mouse granulocyte-macrophage colony-stimulating factor (rmGM-CSF) and synthetic peptide met-enkephalin (M-ENK) against blood-induced Plasmodium berghei infection in Swiss mice was investigated. Mice co-administered with rmGM-CSF (10.0 mug/kg) and M-ENK (2.0 mg/kg) x 3/day, i.p., beginning on day -1 and continuing through day +4 after the initiation of infection, showed significant suppression (p < 0.05) (sometimes even complete elimination) of parasitaemia compared to vehicle-treated controls. However, when administered separately, neither of these agents induced any detectable protective effect. Surprisingly, mice similarly co-administered with rmGM-CSF (10.0 mug/kg) and higher doses of M-ENK (10.0 mg/kg), showed no protection. Polyclonal neutralizing (100%) antibody to rmGM-CSF abrogated the combined protective effect of these agents. Additionally, naloxone (10.0 mg/kg/day x 6, i.p.), a non-selective, opioid receptor antagonist, also blocked the combined protection. Mice that survived the challenge showed a significant increase (p < 0.05) in total circulating leukocytes counts, and the pool-size and the phagocytic activity of both the peritoneal and splenic macrophages, ex vivo. Silica (3.0 mg/mouse, i.v.) abrogated the combined protective effect of rmGM-CSF and M-ENK. These results indicate that co-administration of rmGM-CSF and dose dependent quantities of M-ENK in P. berghei-infected mice can protect against malaria, apparently through macrophage-mediated mechanisms.     

The effects of oral glutamine on cisplatin-induced genotoxicity in Wistar rat bone marrow cells

Several studies have suggested that dietary supplementation with antioxidants can influence the response to chemotherapy as well as the development of adverse side effects that result from treatment with antineoplastic agents. The emphasis of the present study was to investigate whether the administration of a single dose of oral glutamine had any protective effect against cisplatin-induced clastogenicity. Cisplatin was administered to Wistar rats either alone or after treatment with glutamine. The rats were treated with glutamine (300 mg/kg b.w.) by gavage 24h before the administration of cisplatin (5mg/kg b.w., i.p.) and then sacrificed 24h after treatment with cisplatin. Glutamine significantly reduced (by about 48%) the clastogenicity of cisplatin in rat bone marrow cells. The antioxidant action of glutamine presumably modulates the clastogenic action of cisplatin.     

Role of kappa- and delta-opioid receptors in the antinociceptive effect of oxytocin in formalin-induced pain response in mice

Oxytocin has been implicated in the modulation of somatosensory transmission such as nociception and pain. The present study investigates the effect of oxytocin on formalin-induced pain response, a model of tonic continuous pain. The animals were injected with 0.1 ml of 1% formalin in the right hindpaw and the left hindpaw was injected with an equal volume of normal saline. The time spent by the animals licking or biting the injected paw during 0-5 min (early phase) and 20-25 min (late phase) was recorded separately. Oxytocin (25, 50, 100 microg/kg, i.p.) dose dependently decreased the licking/biting response, both in the early as well as the late phases. The antinociceptive effect of oxytocin (100 microg/kg, i.p.) was significantly attenuated in both the phases by a higher dose of the non-selective opioid receptor antagonist naloxone (5 mg/kg, i.p.), MR 2266 (0.1 mg/kg, i.p.), a selective kappa-opioid receptor antagonist and naltrindole (0.5 mg/kg, i.p.), a selective delta-opioid receptor antagonist but not by a lower dose of naloxone (1 mg/kg, i.p.) or beta-funaltrexamine (2.5 microg/mouse, i.c.v.), a selective mu-opioid receptor antagonist. Nimodipine, a calcium channel blocker (1 and 5 mg/kg, i.p.) produced a dose-dependent analgesic effect. The antinociceptive effect of oxytocin was significantly enhanced by the lower dose of nimodipine (1 mg/kg, i.p.) in both the phases. Chronic treatment with oxytocin (100 microg/kg/day, i.p. daily for 7 days) did not produce tolerance in both the phases of formalin-induced pain response. The results thus indicate that oxytocin displays an important analgesic response in formalin test; both kappa- and delta-opioid receptors as well as voltage-gated calcium channels seem to be involved in the oxytocin-induced antinociception.     

Influence of nitric oxide synthase inhibitors on the vasopressin-induced pituitary-adrenocortical activity and hypothalamic catecholamine levels.

In the present study the role of endogenous nitric oxide (NO) in the vasopressin-induced ACTH and corticosterone secretion was investigated in conscious rats. Vasopressin (AVP 5 microg/kg i.p.) considerably augmented ACTH and corticosterone secretion. L-arginine (120 and 300 mg/kg i.p.) did not significantly alter the AVP-induced secretion of those hormones. Nitric oxide synthase (NOS) blockers N(omega)-nitro-L-arginine (L-NNA) and its methyl ester (L-NAME) given i.p. 15 min before AVP markedly increased the AVP-induced ACTH secretion. L-NNA (2 mg/kg) more potently and significantly increased the AVP-induced ACTH secretion, whereas L-NAME elicited a weaker and not significant effect. Both those NOS antagonists intensified significantly and to a similar extent the AVP-induced corticosterone secretion. L-arginine (120 mg/kg i.p.) reversed the L-NNA-induced rise in the AVP-stimulated ACTH secretion and substantially diminished the accompanying corticosterone secretion. Neither vasopressin alone nor in combination with L-arginine and L-NAME evoked any significant alterations in the hypothalamic noradrenaline and dopamine levels. L-NNA (2 and 10 mg/kg i.p.) elicited a dose dependent and significant decrease in the hypothalamic noradrenaline level. The hypothalamic dopamine level was not significantly altered by any treatment. These results indicate that in conscious rats endogenous NO has an inhibitory influence on the AVP-induced increase in ACTH and corticosterone secretion. L-NNA is significantly more potent than L-NAME in increasing the AVP-induced ACTH secretion. This may be connected with a considerable increase by L-NNA of hypothalamic noradrenergic system activation which stimulates the pituitary-adrenal axis in addition to specific inhibition of NOS.     

Measurement of Endogenous Noradrenaline Release in the Rat Cerebral Cortex In Vivo by Transcortical Dialysis: Effects of Drugs Affecting Noradrenergic Transmission

The release of endogenous noradrenaline was measured in the cerebral cortex of the halothane-anesthetized rat by using the technique of brain dialysis coupled to a radioenzymatic assay. A thin dialysis tube was inserted transversally in the cerebral cortex (transcortical dialysis) and perfused with Ringer medium (2 microliter min-1). Under basal conditions, the cortical output of noradrenaline was stable over a period of at least 6 h and amounted to 8.7 pg/20 min (not corrected for recovery). Histological control of the perfused area revealed very little damage and normal morphology in the vicinity of the dialysis tube. Omission of calcium from the perfusion medium caused a marked drop in cortical noradrenaline output. Bilateral electrical stimulation (for 10 min) of the ascending noradrenergic pathways in the medial forebrain bundle caused a frequency-dependent increase in cortical noradrenaline output over the range 5-20 Hz. Stimulation at a higher frequency (50 Hz) resulted in a levelling off of the increase in cortical noradrenaline release. Systemic administration of the dopamine-beta-hydroxylase inhibitor bis-(4-methyl-1-homopiperazinylthiocarbonyl) disulfide (FLA 63) (25 mg/kg i.p.) markedly reduced, whereas injection of the monoamine oxidase inhibitor pargyline (75 mg/kg i.p.) resulted in a progressive increase in, cortical noradrenaline output. d-Amphetamine (2 mg/kg i.p.) provoked a sharp increase in cortical noradrenaline release (+450% over basal values within 40 min). Desmethylimipramine (10 mg/kg i.p.) produced a twofold increase of cortical noradrenaline release. Finally, idazoxan (20 mg/kg i.p.) and clonidine (0.3 mg/kg i.p.), respectively, increased and decreased the release of noradrenaline from the cerebral cortex.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of lactulose and lactitol on coliform bacteria and bacterial translocation in the caecum during 72-h starvation in rats

Lactulose and lactitol, non-absorbable disaccharides, prevent bacterial translocation (BT) arising from the gut. In contrast, lack of food into the gut leads to coliform bacterial overgrowth and even if it does not cause BT, can induce the risk from other stimuli for BT. In this study, we tested whether lactulose and lactitol affected populations of coliform bacteria in the caecum during starvation in Sprague-Dawley rats. Three groups of rats were starved for 72 h and given oral 2 ml undiluted lactulose (670 mg/ml), 2 ml undiluted lactitol (666 mg/ml) or 2 ml physiological saline, respectively, once a day. The caecum and mesenteric lymph nodes (MLNs) were removed for microbiological and histopathological analyses. The highest degree of coliform bacterial overgrowth, BT to MLNs and histopathological damage were observed in lactulose-treated rats, followed by the group treated with lactitol. As a result of this study, both drugs, especially lactulose augmented the proliferation and translocation tendency of coliform bacteria in the caecum during 72-h starvation in rats.