The effect of naloxone on C-fiber reflex in cats

The specific opiate antagonist naloxone rapidly reverses hypotension caused by endotoxin, hypovolemia and spinal transection. The fact that naloxone appears to act as a causative level to improve shock pathophysiology, as well as its extensive clinical use for opiate overdose, makes this drug a particularly clinical use for opiate overdose, makes this drug a particularly attractive potential therapeutic agent for the treatment of shock in humans. The electrophysiological effects of naloxone were studied on c-fiber reflex in spinal and intact cats. The drugs were injected in to the right cephalic vein. Results can be summarized as follows: Naloxone in the intact cat had a more pronounced facilitating effect than in the spinal cat. Naloxone given as a one shot injection was more potentiating than naloxone given as a 5 minute injection. Naloxone antagonized the facilitation of a small dose of ketamine-HCL in the intact cat and also the depression of a large dose ketamine-HCL. Naloxone antagonized capsaicin on c-fiber reflex. This result supports that naloxone has the antagonizable inhibitory effect of substance-P. Naloxone for the first injection had an effective response but additional naloxone did not facilitate the c-fiber reflex.     

Salutary and detrimental effects of the (+)- and (-)enantiomers of meptazinol in anesthetized rats subjected to hemorrhagic shock

The effects of the two enantiomers of the opioid mixed agonist-antagonist meptazinol on mean arterial pressure (MABP), heart rate (HR), and survival time were investigated in pentobarbitone-anesthetized rats subjected to hemorrhagic shock. Following intravenous administration of (+)meptazinol (0.5 mg kg-1) to shocked animals (MABP, 30.0 +/- 0.2 mm Hg), there was significant and gradual elevation of MABP, which at the time the experiment was terminated did not differ significantly from preshock values. In addition, survival was prolonged by up to 7 days. Paradoxically, similar doses of (-)meptazinol produced further falls in MABP, significantly so at 60 min posttreatment. Likewise, the drug produced a slow progressive and significant decline in HR which culminated in premature death (mean survival time, 74.3 +/- 5.9 min, compared with a control value of 104.4 +/- 8.8 min; p less than 0.05). Our results demonstrate that the two enantiomers of meptazinol have opposing effects on hemorrhagic shock sequelae in the rat. It is surprising, in view of its known opioid antagonistic properties, that (-)meptazinol exerted a detrimental effect.     

The effect of fluvoxamine and sertraline on the opioid withdrawal syndrome: a combined in vivo cerebral microdialysis and behavioural study.

A microdialysis study was undertaken to determine the effect of acute and sub-chronic administration of the selective serotonin reuptake inhibitor, fluvoxamine, and the acute effect of the selective serotonin reuptake inhibitor sertraline, on the naloxone precipitated opioid withdrawal induced increase in hippocampal noradrenaline levels. This study also determined the effect of fluvoxamine and sertraline on opioid withdrawal-induced physical behaviours. Naloxone (1 mg kg(-1); i.p.) increased noradrenaline levels in the hippocampus of morphine dependent rats 20 min after administration, with peak levels of 267+/-13% of baseline, occurring 40 min after administration of naloxone. Opioid withdrawal-induced physical behaviours were evident in morphine dependent rats 5 min after a naloxone injection (1 mg kg(-1); i.p.). Acute fluvoxamine or sertraline (10 mg kg(-1); i.p.) given 40 min before naloxone (1 mg kg(-1); i.p.) did not modify the increased hippocampal noradrenaline levels (242+/-15 and 242+/-19%, respectively), observed in morphine dependent rats following an naloxone injection. Acute fluvoxamine and sertraline (10 mg kg(-1); i.p.) reduced the severity of the naloxone precipitated opioid withdrawal syndrome. Sub-chronic treatment with fluvoxamine (10 mg kg(-1); i.p.) prevented the naloxone precipitated increase in hippocampal noradrenaline levels in morphine dependent rats. Furthermore, sub-chronic fluvoxamine produced a significantly reduced baseline level of noradrenaline in these rats which was 52.5+/-8% of baseline 40 min after naloxone.     

The effect of naloxone on cerebellar cGMP content

Summary Naloxone in high doses (60–240 mg/kg i.p.) produced a dose-dependent increase in cerebellar cGMP content of mice. The rise in cGMP content reached its maximum within 5 min and was of short duration. Short-lasting episodes of clonic seizures were noted after 240 mg/kg naloxone. Low doses of naloxone (5–10 mg/kg) had no effect on cerebellar cGMP content, but markedly potentiated the increase in cGMP induced by diazepam, but had only a slight effect on the action of pentobarbital (30 mg/kg i.p.).These results support the assumption proposed by other authors that naloxone exerts GABA antagonistic effects aside from the potent opiate receptor antagonistic activity.     

Mechanism of the protective effects of prostaglandins E1 and F2 alpha in canine endotoxin shock

Prostaglandins E₁ (PGE₁) and F_2α (PGF_2α) were studied for their ability to alter the course of a standardized endotoxin shock procedure in dogs. 3 hr after the administration of E. coli endotoxin, mean arterial blood pressure (MABP) was reduced 44% and cardiac output (CO) 60%. At this time plasma activities of the lysosomal protease, cathepsin D, increased 670%, and of a myocardial depressant factor (MDF), 310%. Dogs treated with PGF_2α had consistently higher MABP and CO, while plasma cathepsin D and MDF activities were moderately elevated. In addition, post-endotoxin survival was significantly improved. PGE₁-treated dogs exhibited a higher MABP and CO, while plasma cathepsin D and MDF activities were only slighly elevated, and survival time increased (p < 0.005). Furthermore, PGE₁, but not PGF_2α markedly reduced the rate of release of proteases from isolated hepatic and pancreatic lysosomes subjected to thermal activation. An enhanced release of splanchnic proteases appears to lead to the formation of MDF, a peptide involved in the pathophysiology of endotoxin shock. Prostaglandin E₁ may protect in endotoxin shock by suppressing the release of lysosomal proteases and the subsequent formation of MDF, whereas PGF_2α may protect either by circulatory support or by some secondary mechanism for preventing the release of lysosomal enzymes.     

The timing of endothelin and nitric oxide inhibition affects survival in a mice model of septic shock

The effect of endothelin and nitric oxide (NO) inhibition on survival from septic shock was investigated in male Swiss albino mice (20-40 g), with particular emphasis on the timing of the administration of their blockers after Escherichia coli endotoxin (lipopolysaccharide, O55:B5, 60 mg kg(-1), i.p.) challenge. Mice were injected with the endothelin receptor antagonist bosentan (30 mg kg(-1), i.p., either 2 or 12 h after endotoxin) alone or in addition to the NO synthase blockers L-canavanine (100 mg kg(-1), i.p.), N(G)-nitro-L-arginine methyl ester (L-NAME, 3 mg kg(-1), i.p.) or aminoguanidine (15 mg kg(-1), i.p.), which were also given twice at 2 and 6 h after endotoxin. Control animals received saline, and survival rates in each group (n=10) were recorded over 24 h at 6-h intervals. At 24 h, the survival rate was 10% in controls, but 30% (n.s.) and 70% (P<0.05) in animals that received only bosentan at 2 and 12 h, respectively, indicating a relatively late involvement of endothelin in comparison to NO. In contrast, these figures were 70% (P<0.05) and 80% (P<0.05) at 12 h for L-NAME and L-canavanine, respectively, and 10% (n.s.) at 24 h, implying a relatively early involvement of NO compared to endothelin. Interestingly, survival in the aminoguanidine group (75% at 24 h, P<0.05 vs. controls) was markedly higher than that in the L-NAME and L-canavanine groups, an effect that was attributed to mechanisms other than NO inhibition. Survival was better (60%, P<0.05 vs. endotoxin alone) when bosentan was given at 2 h in combination with L-NAME, but the best outcome (90% survival, P<0.05) was observed in animals when bosentan was given at 12 h and L-NAME was injected twice at 2 and 6 h. However, the statistical analysis revealed no significant additional beneficial effect of L-NAME coadministered with bosentan. Therefore, we conclude that NO is involved during the earlier phases of septic shock in comparison to a relatively late involvement of endothelin peptides, and that bosentan alone appears to be beneficial when administered at least 12 h after the endotoxin challenge in our mice model of septic shock.     

CARDIAC ANTIARRHYTHMIC EVALUATION OF NALOXONE WITH OR WITHOUT PROPRANOLOL USING A MODIFIED CHLOROFORM-HYPOXIA SCREENING TEST IN THE RAT

The effects of naloxone and propranolol on cardiac arrhythmias and durations from respiratory arrest to ventricular asystole and cardiac standstill were studied in unanaesthetized young rats induced to suffer respiratory arrest and exhibit ventricular fibrillation (VF) by a modified chloroform hypoxia technique. Both naloxone and propranolol reduced the incidence of VF dose dependently, indicating that they have antiarrhythmic effects. Addition of naloxone to propranolol shifted the dose-response curve of propranolol to the left significantly, indicating an additive effect of the two drugs in their antiarrhythmic activity. Both naloxone and propranolol prolonged the duration from respiratory arrest to ventricular asystole. However, joint administration of both did not further prolong this duration indicating an absence of additive effects. Naloxone prolonged the duration from respiratory arrest to cardiac standstill, indicating that naloxone prolonged the survival time. In contrast, propranolol did not produce the same effect. That naloxone both produced antiarrhythmic effect and prolonged the survival time whereas propranolol only corrected cardiac arrhythmias suggests that the antiarrhythmic effect of naloxone may not result in prolongation of survival time and that different mechanisms may be involved in the antiarrhythmic effect.     

Inhibitory effect of morphine on yawning induced by cholinoceptor and dopamine D2 receptor activation in rats.

1. Bromocriptine (2, 4 and 8 mg kg-1, i.p.), physostigmine (0.05, 0.1 and 0.2 mg kg-1, i.p.) and pilocarpine (1, 3 and 5 mg kg-1, i.p.) induced dose-dependent yawning in rats. 2. These responses were reduced in a dose-dependent manner by pretreatment with morphine. 3. The inhibitory effect of morphine was reversed by naloxone. 4. Naloxone alone induced slight but significant yawning. 5. The present results suggest that morphine inhibits yawning in rats at an opiate receptor downstream from the sites at which cholinoceptor and dopamine D2 activation induce yawning. The anatomical location of these sites remains to be established.     

Effects of intravascular volume expansion on the cardiovascular response to naloxone in a canine model of severe endotoxin shock.

The specific opiate receptor antagonist, naloxone, can produce haemodynamic improvement and increased survival in experimental shock. The efficacy of naloxone therapy in a canine model of endotoxin shock has been evaluated both with and without intravascular volume replacement. Animals were anaesthetized with alpha-chloralose and allowed to breathe spontaneously. A large bolus dose of endotoxin was followed by a continuous infusion and treatment was instituted one hour after the endotoxin bolus. In the absence of volume replacement, naloxone caused only limited and transient increases in mean arterial pressure (MAP) and left ventricular (LV) dp/dt max, with little effect on cardiac index (CI). Total peripheral resistance index (TPRI) tended to rise in both control and naloxone-treated dogs. In volume-replaced animals, naloxone produced substantial and sustained increases in the MAP and LV dp/dt max with an associated rise in the CI. TPRI rose initially in this series and then fell progressively. Further analysis of the improvements in the CI showed an increase in stroke index with a tendency for heart rate to fall. These findings suggest a myocardial action of naloxone in endotoxin shock, which is augmented by volume replacement. An initial, transient vasoconstrictor effect cannot, however, be excluded. Further work is required to determine the mechanism of the effects described.     

Effect of naloxone and amphetamine on acquisition and memory consolidation of active avoidance responses in rats

Pretraining IP injection of naloxone (0.3 mg/kg) or amphetamine (2 mg/kg) enhanced performance during acquisition, but did not improve retention of active avoidance responses in rats. Naloxone (0.1 or 3 mg/kg) had no effect on acquisition or on retention. The combination of naloxone (0.3 mg/kg) plus amphetamine (2 mg/kg) did not produce the facilitation observed when each of the two drugs was administered alone. Pretreatment with the higher dose of naloxone (3 mg/kg) blocked the facilitative effect of amphetamine on acquisition. Post-training administration of naloxone (0.3 mg/kg) or amphetamine (2 mg/kg) improved retention. Naloxone (0.1 or 3 mg/kg) had no effect. When naloxone and amphetamine were combined, at respective doses of 0.3 mg/kg and 2 mg/kg, the improvement did not occur, i.e., the higher dose of naloxone prevented the facilitative effect of amphetamine. In addition, an ineffective dose of amphetamine (0.5 mg/kg), given either pre-or post-training together with the lower dose of naloxone (0.1 mg/kg), produced a significant enhancement of acquisition or consolidation, respectively. The results are consistent with the possibility that naloxone might exert its facilitative action on acquisition and memory consolidation through the release of catecholaminergic systems from inhibitory influences of opioids.     

Naloxone antagonizes behavioural effects of d-amphetamine in mice and rats

The influence of naloxone on two characteristic behavioural effects of d-amphetamine has been studied in rodents. Naloxone (0.3, 1 and 3 mg/kg, s.c.) antagonized the increase in spontaneous locomotor activity that is associated with administration of d-amphetamine (2 mg/kg, s.c.) to mice. Naloxone, at 0.3, 1 and 3 mg/kg, subcutaneously (but not at 10 and 30 mg/kg), antagonized d-amphetamine-induced ipsilateral turning in rats lesioned unilaterally with 6-hydroxydopamine in the substantia nigra. It may be postulated that the effect of d-amphetamine in these behavioural models is brought about partially by its activity in releasing an endogenous opiate which acts via an opiate receptor influencing dopaminergic activity (naloxone sensitive) and partially by its activity on dopaminergic neurones (naloxone insensitive).     

Behavioral effects of morphine and naloxone following chronic morphine administration

The effects of morphine, naloxone, and combinations of these drugs were examined in squirrel monkeys under shock-postponement schedules. In the absence of a lever press, shocks could be presented every 4s, and each response postponed shock for 20s. Acutely, morphine (0.10–3.00 mg/kg) produced not only overall response-rate decreases, but also increases in the number of shocks, whereas naloxone (0.10–30.00 mg/kg) had little effect on responding. When given in combination with morphine, several doses of naloxone antagonized the rate-reducing and shock-increasing effects of morphine. Daily administration of morphine resulted in a substantial decrease in the number of shocks received and a moderate attenuation of the rate-decreasing effects of morphine (tolerance). Lower doses substituted for the fixed daily dose resulted in a smaller effect on behavior than under acute administration. Naloxone given in combination with the daily morphine dose or substituted for the daily administration of morphine, produced effects similar to those seen prior to chronic drugging. Thus, behavioral effects of naloxone were not altered even though tolerance to morphine was observed. Larger doses of naloxone continued to antagonize the effects of morphine for at least 24h. No signs of physical dependence were noted when naloxone was administered or when administration of morphine ended.     

The effect of naloxone on some neuroendocrine responses to limb ischaemia

The finding that naloxone reverses the arterial hypotension produced by bacterial endotoxin in the rat was confirmed and the effect of naloxone on the responses to another form of injury, limb ischaemia was studied. Naloxone had no effect on the fall in blood pressure and colon temperature or on behaviour and survival after bilateral hind-limb ischaemia. The ambient temperature threshold for the onset of shivering was depressed by limb ischaemia as in untreated rats. The increases in the plasma concentrations of glucose and corticosterone and the decrease in that of prolactin after limb ischaemia were unaltered by naloxone. In control rats naloxone reduced the ambient temperature threshold for the onset of shivering and the plasma prolactin concentration. It is concluded that the endogenous opioids do not play a very significant part in the responses to ischaemic limb trauma.     

Protective effects of urinary trypsin inhibitor in experimental shock

The effects of human urinary trypsin inhibitor (UTI) were studied in experimental shock models. Administration of 50,000 U/kg, i.v., of UTI protected against mortality from shock induced by burn, endotoxin or trauma. Aprotinin at a dose of 50,000 U/kg improved only endotoxin shock and showed a moderate but not significant effect on burn and traumatic shock. Administration of 50,000 U/kg, i.v., of UTI protected against the aggravation in systemic hemodynamics in canine hemorrhagic shock. Furthermore, in rat traumatic shock, 50,000 U/kg, i.v., administration of UTI significantly reversed the increased serum beta-glucuronidase and trypsin activities and the decreased hepatic ATP level, and it moderately suppressed the increased serum uric acid level. Aprotinin failed to affect all these biochemical changes induced by drum trauma. These results suggest that the protective effect of UTI against experimental shock is possibly exerted through lowering the elevated enzyme activities in the serum during shock.     

In vivo evidence for the selectivity of ICI 154129 for the delta-opioid receptor

The in vivo selectivity of the novel delta opioid-receptor antagonist N,N-bisallyl-Tyr-Gly-Gly-psi-(CH2S)-Phe-Leu-OH (ICI 154129) was examined in several opioid-selective models. Antagonism at the delta receptor was demonstrated in the striatal head-turn model in the rat. Intrapallidal injection of the relatively selective delta-receptor agonist D-Ala2,D-Leu5-enkephalin (0.5 micrograms) slowed the head-turn time and this effect was completely prevented by prior subcutaneous administration of ICI 154129 (30 mg/kg). The role of delta receptors in two classical test situations was studied using the mixed opioid agonist etorphine and the antagonists naloxone and ICI 154129. The drug ICI 154129 (30 mg/kg, s.c.) failed to prevent the antinociceptive effects and stimulation of locomotor activity produced by etorphine, whereas the relatively selective mu-opioid receptor antagonist, naloxone was effective in both test situations. The possible involvement of delta receptors in morphine-induced dependence was studied by monitoring the abstinence behaviour precipitated in rats given pellets of morphine by either ICI 154129 or naloxone. Naloxone (0.5 mg/kg, i.p.) precipitated a characteristic withdrawal syndrome in conscious rats and, at a much smaller dose (0.02 mg/kg, i.p.), induced shaking behaviour in pentobarbitone-anaesthetised rats. No withdrawal signs were observed in either model after injection of ICI 154129 (30 mg/kg, s.c.), suggesting that the delta receptors are not involved in dependence on morphine.     

Effect of the opiate antagonist naloxone on digitalis induced cardiac arrhythmias

To test the hypothesis that the endogenous opioid system is operative in digitalis arrhythmias, guinea pigs anesthetized with pentothal and breathing spontaneously were allocated to a control group or four naloxone groups: 0.1 mg/kg i.v., 1.0 mg/kg i.v., 2 mg/kg i.v. or 4 mg/kg i.v. after the induction of arrhythmias by digoxin 100 micrograms/kg i.v. every 15 min. Naloxone at higher doses resulted in a rapid development of fatal arrhythmias with high degree AV block being more frequent than ventricular tachycardiac or fibrillation. Survival was significantly and inversely related to naloxone dose. The role of the autonomic nervous system was studied using cervical cord transection at the C7 level or bilateral cervical vagotomy, or atropine 1.2 mg/kg pretreatment. Cord transection, but not vagotomy, was associated with a significantly higher digoxin dose to produce arrhythmias. Naloxone 4 mg/kg i.v. shortened survival in cord transected animals, but less than in intact animals. Naloxone did not alter survival in vagotomized animals or animals that were pretreated with atropine. Thus, naloxone accelerates the development of fatal cardiac arrhythmias suggesting that endogenous opioids are involved in digitalis toxic arrhythmias an effect interrelated to the autonomic, mainly parasympathetic, nervous system.     

Cloricromene, a coumarine derivative, protects against lethal endotoxin shock in rats.

Endotoxin shock was induced in male rats by an intravenous (i.v.) injection of Salmonella enteriditis lipopolysaccharide (LPS; 20 mg/kg i.v.). Survival rate, macrophage and serum tumor necrosis factor (TNF-alpha), mean arterial blood pressure (MAP) and white blood cell count were then evaluated. Furthermore the in vitro effect of cloricromene on peritoneal macrophage phagocytosis and TNF-alpha release by primed peritoneal macrophages was investigated. LPS administration caused animal death (0% survival 24 h after endotoxin challenge), hypotension, marked leukopenia and increased the levels of TNF-alpha in both serum and macrophage supernatants. Cloricromene administration (0.5, 1 and 2 mg/kg i.v. 15 min after endotoxin) protected against LPS-induced lethality (100% survival rate 24 h after endotoxin challenge), reverted LPS-induced hypotension and leukopenia, and decreased TNF-alpha in both serum and macrophage supernatants. Finally, cloricromene, added in vitro to peritoneal macrophages collected from endotoxin-treated rats increased macrophage phagocytosis and reduced TNF-alpha formation by activated mononuclear phagocytes. Our data suggest that cloricromene increases survival rate in endotoxin shock through an inhibition of TNF-alpha production.     

静脉注射不同阿片肽拮抗物抗大鼠烫伤休克效果的比较

在大鼠20%体表面积Ⅲ°烫伤后,立即从静脉分别注射beta-内啡肽抗血清10μl,ICI_(174864) 0.2mg,TRH 2mg,或纳洛酮2mg,随后在1,2,3h再分别给予半量,观察心血管功能指标和存活时间。结果表明,beta-内啡肽抗血清、ICI_(174864)和纳洛酮,均可改善烫伤动物的心功能指标,延缓MAP下降和HR减慢,尤其beta-内啡肽抗血清可显著延长动物的存活时间。TRH在早期能增加烫伤动物的心率,延缓MAP的下降,晚期却加快了MAP的下降,对心功能指标几无改善。这提示beta-内啡肽抗血清、ICI_(174864)和纳洛酮,均有抗烫伤休克的作用;TRH如何适当地应用于抗烫伤休克,有待进一步探讨。     

Morphine inhibits dopaminergic and cholinergic induced ejaculation in rats

1. Subcutaneous injection (s.c.) of apomorphine (0.1–0.5 mg/kg) and intraperitoneal administration (i.p.) of quinpirole (0.01–0.25 mg/kg), physostigmine (0.05–0.2 mg/kg) and philocarpine (0.75–3 mg/kg, i.p.) but not neostigmine (0.1–1 mg/kg) induced ejaculation in rats.2. The responses of drugs were reduced by morphine (1–6 mg/kg, s.c.) pretreatment.3. The inhibitory effect of morphine was reversed by naloxone (1.5 mg/kg, s.c.).4. Naloxone (0.75–3 mg/kg, s.c.) alone induced slight but significant ejaculation.5. Ejaculatory responses induced by apomorphine and quinpirole but not those by physostigmine and pilocarpine were reduced by sulpiride (100 mg/kg, i.p.) pretreatment.6. Domperidone (1–30 mg/kg, i.p.) did not change the response induced by apomorphine.7. Pretreatment of animals with the cholinergic antagonist atropine (10 mg/kg, i.p.) decreased the frequency of ejaculation induced by apomorphine, quinpirole, physostigmine or pilocarpine.8. It may be concluded that D-2 activation induces ejaculation through influence on cholinergic mechanisms and morphine inhibits the ejaculation induced by activation of both cholinergic and dopaminergic systems via opiate receptor sites.     

Limitation of polymyxin B on suppression of endotoxin shock induced by Salmonella infection in mice

The protective effects of an antibiotic polymyxin B (PLB), having lipopolysaccharide (LPS)-binding activity, on infection-induced endotoxin shock in mice were investigated. Infection with 10(8) colony forming units of an attenuated Salmonella typhimurium aroA strain caused lethal endotoxin shock to ddY mice. Treatment with PLB 1 h post infection (p.i.) resulted in significant reduction of mortality and bacterial numbers in livers. In addition, treatment with PLB 1 h p.i. resulted in a transient increase at the early stage and gradual decline in plasma LPS levels. Although plasma levels of sCD14 and high mobility group box chromosomal protein-1 (HMGB-1) increased according with progression of infection, increases in plasma levels of sCD14 and HMGB-1 were downregulated by treatment with PLB 1 h p.i. However, the lethal shock was not blocked by treatment with anti-CD14 monoclonal antibody at 3 h and 6 h p.i. Interestingly, administration of PLB 6 h p.i. did not show any protective activities, indicating that a time window for effective PLB action is present.