Characterization of adenosine receptors evoking excitation of mesenteric afferents in the rat

We examined the effects of adenosine receptor agonists and antagonists on the discharge of mesenteric afferent nerves supplying the jejunum in pentobarbitone sodium-anaesthetized rats. Adenosine (0.03-10 mg kg(-1), i.v.), NECA (0.3-300 microg kg(-1), i.v.) and the A1 receptor agonist, GR79236 (0.3-1000 microg kg(-1), i.v.), each induced dose-dependent increases in afferent nerve activity and intrajejunal pressure, hypotension and bradycardia. The A1 receptor antagonist, DPCPX (3 mg kg(-1), i.v.), antagonized all the effects of GR79236 but only the haemodynamic effects of adenosine and NECA. The A2A receptor antagonist, ZM241385 (3 mg kg(-1), i.v.), antagonized the hypotensive effect of NECA but none of the effects of GR79236. The A2A receptor agonist, CGS21680 (0.3-300 microg kg(-1), i.v.), and the A3 receptor agonist, IB-MECA (0.3-300 microg kg(-1), i.v.), each induced only a dose-dependent hypotension. Subsequent administration of adenosine (3 mg kg(-1), i.v.) induced increases in afferent nerve activity and intrajejunal pressure and bradycardia. ZM241385 (3 mg kg(-1), i.v.) antagonized the hypotensive effect of CGS21680 but not the effects of adenosine. Bethanechol (300 microg kg(-1), i.v.) evoked increases in afferent nerve activity and intrajejunal pressure, hypotension and bradycardia. However, adenosine (3 mg kg(-1), i.v.) evoked greater increases in afferent nerve activity than bethanechol despite inducing smaller increases in intrajejunal pressure. In summary, A1 and A2B and/or A2B-like receptors evoke adenosine-induced increases in mesenteric afferent nerve activity and intrajejunal pressure in the anaesthetized rat. Furthermore, elevations in intrajejunal pressure do not wholly account for adenosine-evoked excitation of mesenteric afferent nerves.     

A German-Swedish collection of histopathological slides from 1893

We investigated the effects of KF19514 (5-phenyl-3-(3-pyridyl)methyl-3H-imidazo[4,5-c][1,8]naphthyridin-4 (5H)-one) on bronchoconstriction and allergic inflammation in guinea pigs and on tumor necrosis factor-alpha production in mice. KF19514 inhibited phosphodiesterase 4 (IC50 = 0.40 microM) and phosphodiesterase 1 (IC50 = 0.27 microM) derived from canine tracheal smooth muscles. KF19514 relaxed contracted tracheal smooth muscle and had a potent inhibitory effect on antigen-induced bronchoconstriction (EC50 = 0.058 microM) in vitro. Intravenous administration of KF19514 inhibited histamine-induced bronchoconstriction (ID50 = 2.8 microg/kg i.v.). Moreover, oral administration of KF19514 inhibited anaphylactic bronchoconstriction (ID50 = 0.2 mg/kg p.o.), and eosinophil infiltration in airway stimulated with platelet-activating factor (PAF) or antigen. KF19514 also produced a significant inhibition of tumor necrosis factor-alpha production in mice (ID50 = 0.023 mg/kg p.o.). Finally, KF19514 completely inhibited antigen-induced hyperreactivity at 0.1 mg/kg p.o. These results demonstrate that KF19514 may have efficacy in the treatment of asthma.     

Novel approach for enhancing atrioventricular nodal conduction delay mediated by endogenous adenosine

The 2-amino-3-benzoylthiophene derivative PD 81,723 potentiates the A1 receptor-mediated negative dromotropic effect of exogenous adenosine and adenosine receptor agonists in guinea pig isolated perfused and in situ hearts. The objective of this study was to determine whether PD 81,723 could amplify the cardiac actions of endogenous adenosine. Two approaches known to increase the myocardial interstitial concentration of adenosine--hypoxia, which increases the production of adenosine and the inhibition of adenosine kinase, which decreases its metabolism--were used to test this hypothesis. In guinea pig hearts in situ, PD 81,723 (2 mg/kg i.v.) potentiated the atrioventricular (AV) nodal conduction delay caused by hypoxemia (PaO2, 14 to 19 mm Hg). In guinea pig isolated hearts, PD 81,723 (5 mumol/L) increased by twofold the stimulus-to-His bundle (S-H) interval prolongations induced by both a 5-minute period of hypoxia (25% O2/70% N2/5% CO2) and the administration of the adenosine kinase inhibitor iodotubercidin (40 to 70 nmol/L) but had no effect on coronary conductance. Hypoxia and hypoxia plus PD 81,723 (5 mumol/L) caused equivalent increases in the concentration of adenosine in epicardial transudate, from 0.13 +/- 0.15 to 0.48 +/- 0.1 and 0.45 +/- 0.4 mumol/L, respectively. Similar to the allosteric enhancer, the nucleoside uptake blocker draflazine (0.1 mumol/L) also increased by twofold the S-H interval prolongation caused by hypoxia. In contrast to the allosteric enhancer, draflazine increased the concentration of adenosine in epicardial transudate during hypoxia from 0.48 +/- 0.15 to 1.5 +/- 0.4 mumol/L. Draflazine also increased coronary conductance by approximately twofold in guinea pig normoxic constant-fold perfused hearts.(ABSTRACT TRUNCATED AT 250 WORDS)     

N2733, 1-[3-(3-pyridyl)-acryloyl]-2-pyrrolidinone hydrochloride inhibits LPS-induced TNF-alpha production and improves survival in endotoxemic mice

N2733, 1-[3-(3-pyridyl)-acryloyl]-2-pyrrolidinone hydrochloride, was examined for its effect on TNF-alpha production by human myeloid THP-1 cells stimulated with lipopolysaccharide (LPS). N2733 inhibited LPS-induced release of TNF-alpha from THP-1 cells with an IC50 of 11 microM. N2733 did not affect the cell viability at the concentration of 50 microM or 100 microM. This indicates that N2733 is a potent inhibitor for TNF-alpha production without severe cytotoxicity. N2733 was also studied in two murine endotoxin shock models induced with LPS. One model was DBA/2 mice injected with LPS (5.6 mg/kg, i.v.), which increased the serum level of TNF-alpha within 1 hr. Treatment of these mice with N2733 (100 mg/kg x 2, i.p.) decreased the serum level of TNF-alpha significantly. Another model was DBA/2 mice induced with LPS (30 mg/kg, i.v.), which reduced the survival rate to 30% during 7 days. Administrations of 30 mg/kg and 100 mg/kg N2733 (i.v.) restored the survival rates to 60% and 90% respectively. Our data demonstrate that N2733 inhibits LPS-induced TNF-alpha production, and this response is associated with an improvement in the survival rate of endotoxemic mice.     

Evidence for the presence of both P1 and P2 purinoceptors in the rat myometrium

1. Adenosine, adenosine triphosphate (ATP) and some stable analogues of adenosine inhibited field stimulation-induced contractions of the uterus from rats treated with oestradiol cypionate (20 micrograms/kg, s.c.) 1 day previously. Adenosine was twice as potent as ATP; both were potentiated by dipyridamole (10 mumol/L). 2. The order of agonist potency of adenosine and its analogues was: 5'-N-ethylcarboxamidoadenosine (NECA) > N6-cyclohexyladenosine > or = R-phenylisopropyladenosine = S-phenylisopropyladenosine = 2-chloroadenosine > or = adenosine > or = ATP > > 2-p-(2-carboxyethyl) phenethylamino-5'-N-ethylcarboxamidoadenosine. This order suggests the presence of P1 purinoceptors of the A2B subtype. 3. Responses to agonists were antagonized to differing extents by the P1 purinoceptor antagonist 8-phenyltheophylline (10 mumol/L). 4. In uterine preparations from rats pretreated for 2 days with oestrogen (20 micrograms/kg, s.c.) and for 1 day with progesterone (3 mg/animal, s.c.), the inhibitory potencies of adenosine and NECA were reduced, indicating hormonal regulation of uterine responsiveness to P1 purinoceptor agonists. 5. Stable analogues of ATP caused contractions of unstimulated myometrial preparations from oestrogen-treated animals, indicating activation of a P2 purinoceptor, possibly of the P2X subtype, because of the relative order of potency was alpha, beta-methylene ATP > beta, gamma-methylene ATP = ATP = 2-methylthio ATP.     

In vivo functional interaction between phencyclidine binding sites and sigma receptors to produce head-weaving behavior in rats

To investigate the in vivo functional interaction between phencyclidine (1-(1-phenylcyclohexyl)piperidine; PCP) binding sites and sigma receptors, we examined the effects of sigma receptor ligands on stereotyped head-weaving behavior induced by PCP, a putative PCP/sigma receptor ligand, and (+)-5-methyl-10,11-dihydroxy-5H-dibenzo(a,d)cyclo-hepten-5,10-imin e ((+)-MK-801; dizocilpine), a selective PCP binding site ligand, in rats. PCP (7.5 mg/kg, i.p.)-induced head-weaving behavior was inhibited by both N,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)-phenyl]-ethylamine (NE-100; 0.03-1.0 mg/kg, p.o.), a selective sigma1 receptor ligand, and alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperidine butanol (BMY-14802; 3 and 10 mg/kg, p.o.), a prototype sigma receptor ligand, in a dose-dependent manner, whereas NE-100 (0.1-1.0 mg/kg, p.o.) and BMY-14802 (3 and 10 mg/kg, p.o.) did not inhibit dizocilpine (0.25 mg/kg, s.c.)-induced head-weaving behavior. These results suggest that NE-100 and BMY-14802 act via sigma receptors. Dizocilpine-induced head-weaving behavior was potentiated by 1,3-di-o-tolyl-guanidine (DTG; 0.03-0.3 microg/kg, i.v.) and (+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine ((+)-3-PPP; 3 and 6 mg/kg, i.p.), sigma1/sigma2 receptor ligands, as well as by (+)-N-allyl-normetazocine ((+)-SKF-10,047: 8 mg/kg, i.p.), a sigma1 receptor ligand, while DTG (0.3 microg/kg, i.v.), (+)-3-PPP (6 mg/kg, i.p.) and (+)-SKF-10,047 (8 mg/kg, i.p.) did not induce this behavior. Potentiation of dizocilpine-induced head-weaving behavior by DTG (0.3 microg/kg, i.v.), (+)-3-PPP (6 mg/kg, i.p.) and (+)-SKF-10,047 (8 mg/kg, i.p.) was completely blocked by NE-100 (0.1 mg/kg, p.o.) and BMY-14802 (10 mg/kg, p.o.). These results suggest that PCP binding sites and sigma receptors are involved in PCP-induced head weaving behavior, and that sigma1 receptors play an important role in modulation of the head-weaving behavior.     

Cyclic GMP but not cyclic AMP prevents renal platelet accumulation after ischemia-reperfusion in anesthetized rats

Platelets have been implicated in the pathophysiology of ischemia-reperfusion injury. In this study, antiplatelet effects of cyclic GMP (cGMP)- and cyclic AMP (cAMP)-mediated agents were evaluated in renal ischemia in pentobarbital-anesthetized rats. Renal ischemia was induced by unilateral occlusion of the left renal artery (40 min) followed by reperfusion (30 min) with the contralateral kidney serving as control. 111Indium-labeled platelets, drugs or vehicle were administered 30 min before induction of renal ischemia. Occlusion of the left renal artery for 20, 40 or 60 min resulted in a 100, 300 and 600% increase (over contralateral right kidney) in the platelet-associated 111indium activity in the ischemic kidney. In all subsequent studies the kidney was occluded for 40 min to test the antiplatelet activity of individual agents. 8-Br-cGMP (0.1 and 0.3 mg/kg/min i.v.), zaprinast (0.1 mg/kg/min i.v.) and sodium nitroprusside (0.003 and 0.01 mg/kg/min i.v.) significantly attenuated platelet accumulation in renal ischemia, whereas 8-Br-cAMP (0.3 mg/kg/min i.v.) or milrinone (0.1 mg/kg i.v. bolus, plus 0.01 mg/kg/min) did not. Minoxidil (0.01 and 0.03 mg/kg/min i.v.), a vasodilator which produced equihypotensive effects as the cGMP-mediated agents, and milrinone failed to prevent platelet accumulation. These results demonstrate that modulation of the platelet function by cGMP agents can be dissociated from their blood pressure lowering effects. cGMP is known to inhibit both platelet adhesion and aggregation, whereas cAMP is only active against aggregation. The present findings provide further evidence that cGMP-mediated drugs may afford effective antiplatelet action in an in vivo model of ischemia-reperfusion injury.     

Immediate implantation into the posterior maxilla after antroplasty: the Cranin-Russell Operation

KW-2149 is a new derivative of mitomycin C (MMC). The plasma concentrations, distribution, metabolism, and excretion of [3H]-KW-2149 in normal and tumor-bearing mice after i.v. administration of 16.6 mg/kg were investigated. The plasma radioactivity decreased biexponentially after i.v. administration in normal mice. However, the unchanged drug disappeared rapidly, showing a half-life (t1/2) of 9.7 min, which was shorter than MMC's (18 min). The radioactivity was excreted in mouse urine (33%) and feces (58%) within 144 h. High radioactivity was distributed in the gallbladder, liver, kidney, pancreas, and lung at 1 h after i.v. administration to normal mice. The tumor concentration was lower than the plasma or blood concentration. The lowest radioactivity was observed in the brain. The metabolic rate of KW-2149 was very rapid. The methyl sulfide form (M-16), the symmetrical disulfide dimer (M-18), and the albumin conjugate were detected in plasma, which possessed anticellular activity. The specific anticellular activity of these compounds against uterine carcinoma (HeLa S3) was 1/100, 1, and 1/20 respectively, as compared with that of KW-2149.     

Midline cervical cleft

The effect of m-chlorophenylbiguanide, a selective 5-HT3 receptor agonist, on gastric antral motility was investigated in conscious dogs with a force transducer implanted chronically. m-Chlorophenylbiguanide (0.1-1 mg/kg i.v.) dose dependently enhanced antral motility in the fasted state, and the amplitude of m-chlorophenylbiguanide (1 mg/kg i.v.)-induced antral contractions reached the level of natural phase III contractions. In contrast, m-chlorophenylbiguanide reduced the amplitude of antral contractions in the fed state. A selective 5-HT3 receptor antagonist, ramosetron (0.0003-0.03 mg/kg i.v.), inhibited both effects of m-chlorophenylbiguanide. m-Chlorophenylbiguanide (1 mg/kg i.v.)-induced contractions were inhibited by atropine (0.03 or 0.1 mg/kg i.v.). These results indicate that pharmacological activation of 5-HT3 receptors has opposite effects on canine gastric antral motility in the fasted and in the fed state, being stimulatory and inhibitory, respectively. The stimulatory effect seems to be mediated mainly via the release of acetylcholine.     

The foot in hereditary motor and sensory neuropathies in children

We investigated the regulation of COX-2 expression and activity by adenosine receptors in rat microglial cells. The selective adenosine A2a-receptor agonist CGS21680 and the non-selective adenosine A1- and A2-receptor agonist 5'-N-ethylcarboxiamidoadenosine (NECA) induced an increase in COX-2 mRNA levels and the synthesis of prostaglandin E2 (PGE2). The adenosine A1-receptor agonist cyclopentyladenosine (CPA) was less potent, and the adenosine A1-receptor-specific agonist N6-2-(-aminophenylo)ethyladenosine (APNEA) showed only marginal effects. Microglia expressed adenosine A1-, A2a-, and A3-, but not A2b-receptor mRNAs, whereas astroglial cells expressed adenosine A2b- but not A2a-receptor mRNA. The adenosine A2a-receptor selective antagonist (E)-8-(3,4-dimethoxystyryl)-1,3-dipropyl-7-methylxanthine (KF17837) inhibited both CGS21680-induced COX-2 expression and PGE2 release. CGS21680-increased PGE2 levels were inhibited by dexamethasone, by the nonsteroidal antiinflammatory drug meloxicam, and by the adenylyl cyclase inhibitor 9-(tetrahydro-2-furanyl)-9H-purine-6-amine (SQ22536). CGS21680 and NECA both increased intracellular cAMP levels in microglial cells. Dibutyryl cAMP as well as forskolin induced the release of PGE2. The results strongly suggest that adenosine A2a-receptor-induced intracellular signaling events cause an up-regulation of the COX-2 gene and the release of PGE2. Apparently, the cAMP second messenger system plays a crucial role in COX-2 gene regulation in rat microglial cells. The results are discussed with respect to neurodegenerative disorders of the CNS such as Alzheimer's disease, in which activated microglia are critically involved and COX inhibitors may be of therapeutic benefit.     

Antidepressant-like effects of endogenous histamine and of two histamine H1 receptor agonists in the mouse forced swim test

1. Effects of substances which are able to alter brain histamine levels and two histamine H1 receptor agonists were investigated in mice by means of an animal model of depression, the forced swim test. 2. Imipramine (10 and 30 mg kg(-1), i.p.) and amitriptyline (5 and 15 mg kg(-1), i.p.) were used as positive controls. Their effects were not affected by pretreatment with the histamine H3 receptor agonist, (R)-alpha-methylhistamine, at a dose (10 mg kg(-1), i.p.) which did not modify the cumulative time of immobility. 3. The histamine H3 receptor antagonist, thioperamide (2-20 mg kg(-1), s.c.), showed an antidepressant-like effect, with a maximum at the dose of 5 mg kg(-1), which was completely prevented by (R)-alpha-methylhistamine. 4. The histamine-N-methyltransferase inhibitor, metoprine (2-20 mg kg(-1), s.c.), was effective with an ED50 of 4.02 (2.71-5.96) mg kg(-1); its effect was prevented by (R)-alpha-methylhistamine. 5. The histamine precursor, L-histidine (100-1000 mg kg(-1), i.p.), dose-dependently decreased the time of immobility [ED30 587 (499-712) mg kg(-1)]. The effect of 500 mg kg(-1) L-histidine was completely prevented by the selective histidine decarboxylase inhibitor, (S)-alpha-fluoromethylhistidine (50 mg kg(-1), i.p.), administered 15 h before. 6. The highly selective histamine H1 receptor agonist, 2-(3-trifluoromethylphenyl)histamine (0.3-6.5 microg per mouse, i.c.v.), and the better known H1 agonist, 2-thiazolylethylamine (0.1-1 microg per mouse, i.c.v.), were both dose-dependently effective in decreasing the time of immobility [ED50 3.6 (1.53-8.48) and 1.34 (0.084-21.5) microg per mouse, respectively]. 7. None of the substances tested affected mouse performance in the rota rod test at the doses used in the forced swim test. 8. It was concluded that endogenous histamine reduces the time of immobility in this test, suggesting an antidepressant-like effect, via activation of H1 receptors.     

Alterations in adriamycin efficacy by phenobarbital

Adriamycin dosage should be reduced in patients with impaired liver function, since adriamycin disposition is influenced by liver metabolism and biliary excretion. It follows that drugs that increase the metabolism or excretory capacity of the liver may decrease adriamycin concentrations to suboptimal values. Adriamycin metabolism was therefore studied in mice pretreated with phenobarbital (75 mg/kg i.v.) by injection. After an i.v. dose of adriamycin (30 mg/kg i.v.), plasma fluorescence due to drug and metabolites was less and disappeared at a greater rate in phenobarbital-pretreated mice than control animals. When extracted with chloroform: isoprophyl alcohol (1:1), the livers from the phenobarbital-pretreated group yielded a greater concentration of glycones. Experiments with liver microsomes confirmed that aglycone production occurred at a more rapid initial rate in phenobarbital-induced livers. No increase in aldoketo reductase (daunorubicin reductase) activity was noted. Phenobarbital-pretreated mice, inoculated i.p. with 1 million L1210 cells and then treated with adriamycin (6 mg/kg i.v.), had significantly lower survival than did controls (p less than 0.01). These findings show that phenobarbital affects the disposition of adriamycin by microsomal enzyme induction and suggest that drugs that induce microsomal enzymes should not be used concurrently with adriamycin if optimal drug efficacy is desired.     

Attenuation of Fos-like immunoreactivity in the trigeminal nucleus caudalis following trigeminovascular activation in the anaesthetised guinea-pig

The present study has examined the involvement of sensory neurotransmitters in activating neurones in the trigeminal nucleus caudalis following stimulation of the trigeminovascular system in anaesthetised guinea-pigs. Electrical stimulation of the right trigeminal ganglion produced a unilateral expression of Fos-like immunoreactivity (Fos-LI) in the trigeminal nucleus caudalis. The tachykinin NK1 receptor antagonist, GR205171 (100 micrograms/kg i.v.) and the N-methyl-D-aspartate (NMDA) receptor antagonist, MK-801 (1 mg/kg i.v.) each inhibited expression of Fos-LI following electrical stimulation. The calcitonin gene-related peptide (CGRP) receptor antagonist, CGRP8-37 (1.3 mg/kg i.v.), administered following rostral intracarotid infusion of mannitol to disrupt the blood-brain barrier, tended to reduce Fos-LI evoked by electrical stimulation, although this failed to reach statistical significance. Capsaicin (10 nmol in 0.1 ml), administered intracisternally, produced a bilateral expression of Fos-LI in the trigeminal nucleus caudalis. This expression was unaffected by the peripherally acting NK1 receptor antagonist, GR82334 (0.2 mg/kg i.v.) or CGRP8-37 (1.3 mg/kg i.v.). The centrally penetrant NK1 receptor antagonist, GR205171 (100 micrograms/kg i.v.), inhibited significantly Fos-LI evoked by intracisternal capsaicin administration. It is concluded that the sensory neurotransmitters, substance P and glutamate are released centrally following activation of the trigeminovascular system and that each may be involved in activation of cells in the trigeminal nucleus caudalis.     

Resuscitating effect of melanocortin peptides after prolonged respiratory arrest

1. The resuscitating activity of melanocortin peptides (MSH-ACTH peptides) was tested in an experimental model of prolonged respiratory arrest. 2. Anaesthetized, endotracheally intubated rats subjected to a 5 min period of ventilation interruption, invariably died from cardiac arrest within 6-9 min of resumption of ventilation. 3. When resumption of ventilation was associated with the simultaneous intravenous (i.v.) injection of a melanocortin peptide (alpha-MSH or ACTH-(1-24)) (160 microg kg(-1) there was an almost immediate (within 1 min), impressive increase in cardiac output, heart rate, mean arterial pressure (+ 560% of the before-treatment value) and pulse pressure (+356% of the before-treatment value), with full recovery of electroencephalogram after 30-45 min. Blood gases and pH were normalized within 15-60 min after treatment, and all treated animals eventually recovered completely and survived indefinitely (= more than 15 days). 4. The same response was observed in adrenalectomized animals, as well as in animals pretreated with a beta1-adrenoceptor blocking agent (atenolol, 3 mg kg(-1), i.v.), or with an alpha1-adrenoceptor blocking agent (prazosin, 0.1 mg kg(-1), i.v.), or with an adrenergic neurone blocking agent (guanethidine, 10 mg kg(-1), intraperitoneally). 5. An effect quite similar to that produced by melanocortins was obtained with ouabain (0.1 mg kg(-1), i.v.); the antioxidant drug, glutathione (75 mg kg(-1), i.v.) also produced 100% resuscitation, but the effect was slower in onset. On the other hand, adrenaline (0.005 mg kg(-1), i.v.) was able to resuscitate only 1 out of 8 rats and dobutamine (0.02 mg kg(-1), i.v.) resuscitated 4 out of 8 rats; moreover, the effect of both catecholamines was much slower in onset than that of melanocortins and the initial, impressive stimulation of cardiovascular function was absent. 6. These results show that melanocortin peptides have a resuscitating effect in a pre-terminal condition produced in rats by prolonged asphyxia. This effect seems primarily due to the restoration of cardiac function, not mediated by catecholamines. These data also suggest that these peptides may have potential therapeutic value in conditions of transient cardiac hypoxia and re-oxygenation such as occur in coronary artery disease.     

Poor periodontal health of the pregnant woman as a risk factor for low birth weight

1. It has been hypothesized that 5-HT1A autoreceptor antagonists may enhance the therapeutic efficacy of SSRIs and other antidepressants. Although early clinical trials with the beta-adrenoceptor/5-HT1 ligand, pindolol, were promising, the results of recent more extensive trials have been contradictory. Here we investigated the actions of pindolol at the 5-HT1A autoreceptor by measuring its effect on 5-HT neuronal activity and release in the anaesthetized rat. 2. Pindolol inhibited the electrical activity of 5-HT neurones in the dorsal raphe nucleus (DRN). This effect was observed in the majority of neurones tested (10/16), was dose-related (0.2-1.0 mg kg(-1), i.v.), and was reversed by the 5-HT1A receptor antagonist, WAY 100635 (0.1 mg kg(-1), i.v.), in 6/7 cases tested. 3. Pindolol also inhibited 5-HT neuronal activity when applied microiontophoretically into the DRN in 9/10 neurones tested. This effect of pindolol was current-dependent and blocked by co-application of WAY 100635 (3/3 neurones tested). 4. In microdialysis experiments. pindolol caused a dose-related (0.8 and 4 mg kg(-1), i.v.) fall in 5-HT levels in dialysates from the frontal cortex (under conditions where the perfusion medium contained 1 microM citalopram). In rats pretreated with WAY 100635 (0.1 mg kg(-1), i.v.), pindolol (4 mg kg(-1), i.v.) did not decrease, but rather increased 5-HT levels. 5. We conclude that, under the experimental conditions used in this study, pindolol displays agonist effects at the 5-HT1A autoreceptor. These data are relevant to previous and ongoing clinical trials of pindolol in depression which are based on the rationale that the drug is an effective 5-HT1A autoreceptor antagonist.     

Adenosine A1 and A2 receptor agonists significantly prevent the electroencephalographic effects induced by MK-801 in rats

Both N6-cyclopentyladenosine (CPA, adenosine A1 receptor agonist) and 2-[4-(2-carboxyethyl)phenethylamino]-5'-N-ethylcarboxamido-adenosi ne (CGS 21680, adenosine A2 receptor agonist) inhibited the electroencephalographic (EEG) effects induced by the noncompetitive NMDA receptor antagonist (+)-5-methyl-10,11-dihydro-5H-dibenzo-(a,d)cyclohepten-5,10-imine maleate (MK-801) in rats. While the inhibitory effects of CPA were evident at doses (0.1 and 0.5 mg/kg i.p.) devoid of intrinsic behavioral effects, CGS 21680 was effective only when administered at depressant doses (2 mg/kg i.p.). Since the effects induced by NMDA receptor antagonists may be regarded as a model of psychosis, these results suggest a possible role of adenosine receptor agonists as antipsychotics.     

Effects of mu and delta opioid agonists and antagonists on affective vocal and reflexive pain responses during social stress in rats

The present experiments evaluated the influence of intraventricular mu and delta opioid receptors on affective vocal and reflexive responses to aversive stimuli in socially inexperienced, as well as defensive and submissive responses in defeated, adult male Long-Evans rats. Defeat stress consisted of: (1) an aggressive confrontation in which the experimental intruder rat exhibited escape, defensive and submissive behaviors [i.e., upright, supine postures and ultrasonic vocalizations (USV)], and subsequently, (2) protection from the resident stimulus rat with a wire mesh screen for 10-20 min. Defeat stress was immediately followed by an experimental session with tactile startle (20 psi). The mu opioid receptor agonists morphine (0.1-0.6 microg i.c.v.) and [D-Ala2-N-Me-Phe4-Gly5-ol]-enkephalin (DAMGO; 0.01-0.3 microg i.c.v.), and the delta opioid receptor agonist [D-Pen2,5]-enkephalin (DPDPE; 10-100 microg i.c.v.) dose-dependently decreased startle-induced USV and increased tail-flick latencies in socially inexperienced and defeated rats. Of greater interest, morphine, DAMGO and DPDPE increased the occurrence of the submissive crouch posture, and defeated rats were more sensitive than socially inexperienced rats to the startle-induced USV-suppressive and antinociceptive effects of morphine and DPDPE. The antinociceptive effects of DAMGO were likewise obtained at lower doses in defeated rats. Finally, the USV-suppressive effects of morphine and DAMGO were reversed with the mu receptor antagonist naltrexone (0.1 mg/kg i.p.), but the USV-suppressive effects produced by DPDPE were not reversed with the delta receptor antagonist naltrindole (1 mg/kg i.p.). These results confirm mu, but not delta opioid receptor activation as significant in affective vocal, passive-submissive behavior, as well as reflexive antinociception. Furthermore, similar to previous studies with restraint and electric shock stress, the facilitation of mu opioid effects on vocal responses and antinociception is consistent with the proposal that defeat stress activated endogenous opioid mechanisms.     

Pharmacokinetics of ceftiofur and metabolites after single intravenous and intramuscular administration and multiple intramuscular administrations of ceftiofur sodium to dairy goats

Twelve (12) lactating dairy goats (46-71 kg body wt at study initiation) were divided into four treatment groups and dosed with ceftiofur sodium at 1.1 mg ceftiofur free acid equivalents (CFAE)/kg or 2.2 CFAE/kg using a complete two route (intravenous, i.v.; intramuscular, i.m.), two-period crossover design, with a 2-week washout between injections. After another 2-week washout period, the goats were dosed with ceftiofur sodium i.m. for 5 consecutive days at either 1.1 or 2.2 mg CFAE/kg. The goats from the 2.2 mg/kg multiple dose group were dried off and the i.v. kinetic study repeated. After all injections, blood samples were obtained serially for determination of combined serum concentrations of ceftiofur and metabolites. After intravenous doses of 1.1 and 2.2 mg/kg, the harmonic means of the terminal phase half-lives were 171.8 and 233 min, respectively, for lactating does. The harmonic mean of the terminal phase half-life after an i.v. dose of 2.2 mg/kg in non-lactating does was 254 min. The AUC0-infinity was significantly less and the clearance significantly greater during lactation. After i.m. doses of 1.1 and 2.2 mg/kg, the harmonic mean terminal phase half-lives were 163 and 156 min, respectively. The i.m. bioavailability of ceftiofur sodium in goats was 100%, and the AUC0-infinity was dose-proportional from 1.1-2.2 mg CFAE/kg body weight. After five daily i.m. doses of ceftiofur sodium at either 1.1 or 2.2 mg CFAE, there was minimal accumulation of drug in serum as assessed by Cmax, and serum concentrations were dose-proportional after the multiple dosing regimen.     

Intrathecally administered baclofen for treatment of children with spasticity of cerebral origin

To determine the relative importance of CCK-A, CCK-B, and opioid receptors in mediating the antinociceptive actions of cholecystokinin, we evaluated the actions of selective agonists and antagonists in the mouse hot plate assay. The agonists used were CCK (1-30 nmol i.c.v.), a CCK-A receptor agonist (SNF9019; 0.3-10 nmol i.c.v.), and a CCK-B receptor agonist (SNF9007; 0.3-10 nmol i.c.v.). The antagonists used were the CCK-A receptor antagonist, L364,718 (12.5 nmol i.c.v.), CCK-B receptor antagonist, L365,260 (2.5-25 nmol i.c.v.), and the nonselective opioid receptor antagonist naloxone (1 mg/kg s.c.). CCK and its receptor-selective analogues, SNF9019 and SNF9007, resulted in antinociception that was blocked by naloxone, but was not antagonized by L364,718 or L365,260. In contrast, in positive control experiments, the inhibitory effects of CCK, SNF9019, and SNF9007 on gastrointestinal propulsion in mice were antagonized by identical i.c.v. doses of L364,718 and L365,260. We conclude that centrally administered CCK produces antinociception in the mouse hot plate assay via opioid receptors, but independent of CCK-A or CCK-B receptors. It is necessary to speculate that other CCK receptors, not antagonized by currently available selective antagonists, may exist.     

Attenuation of hypoxia-induced increases in ventilation by adenosine antagonists in rhesus monkeys

The respiratory effects of caffeine and paraxanthine, two xanthine adenosine antagonists with phosphodiesterase (PDE) activity, CGS 15943, a non-xanthine adenosine antagonist lacking PDE inhibitory activity, and rolipram, a non-xanthine PDE inhibitor lacking adenosine antagonist activity, were characterized in unanesthetized, seated rhesus monkeys exposed to 10% O2 balanced in N2 (hypoxia). Ventilation was measured continuously by enclosing the monkey's head in a fitted helmet and using a pressure-displacement plethysmographic technique. Respiratory frequency (f) and minute volume (VE) increased during 15-minute periods of hypoxia, and intramuscular administration of caffeine (0.3 and 1.0 mg/kg), paraxanthine (0.3 and 1.0 mg/kg) and CGS 15943 (0.03 and 0.1 mg/kg) attenuated the ventilatory response to hypoxia. In contrast, rolipram (0.003-0.03 mg/kg) did not significantly alter the ventilatory response to hypoxia. Drug effects also were characterized in monkeys exposed to air (normoxia) or 3%, 4% and 5% CO2 balanced in air (hypercapnia). Doses of caffeine, paraxanthine or CGS 15943 that attenuated the ventilatory response to hypoxia had no significant effect on f or VE during conditions of normoxia or hypercapnia. The results indicate that adenosine may play a major role in the function of peripheral, O2-sensitive mechanisms during hypoxia.