Pilocarpine, food deprivation, and induction of mouse killing by cats

Effects of three treatments that induce mouse killing by rats were examined with cats. Food deprivation induced about 50% killing after 24 hr and almost 100% killing by 27 hr. Pilocarpine (at doses of 1.0 mg/kg that produced marked side-effects, and whether or not methyl atropine pretreatment blocked those side-effects) and chlordiazepoxide (at doses of 1.0--2.0 mg/kg) did not induce any killing. Pilocarpine produced a dose-related inhibition of spontaneous mouse killing (as it does in rats), but this was antagonised by methyl atropine. The side-effects of pilocarpine and chlordiazepoxide did not seem to account for their failure to induce killing. In contrast with food deprivation, the mechanisms by which pilocarpine and chloridazepoxide induce killing in rats may not have homologs in cats.     

Suppression of mouse killing by lateral hypothalamic infusion of atropine sulfate in the rat: A general behavioral suppression

Male hooded rats which had been induced to kill mice by food deprivation had intracranial cannulas implanted into the lateral hypothalamus. Injections of 3 μl to each side of the brain blocked mouse killing in 12 out of 15 animals when the injected substance was the general blocking agent lidocaine. Atropine sulfate produced a significant suppression of mouse killing at a dose of 15 μg to each hemisphere but not with doses of 1.8 or 6.0 μg. The 15 μg but not the 1.8 μg dose also suppressed food intake. It is argued that the cholinergic antagonist atropine sulfate only suppresses mouse killing at high doses which produce a general suppression of behavior.     

Oxazepam induced mouse killing by rats

Oxazepam (2.5-80 mg/kg) induced significant mouse killing among large samples (N = 100/dose) of Holtzman strain albino rats. Meprobamate (2.5-80 mg/kg) and Chlorpromazine (0.5-4 mg/kg) did not induce killing. Despite its lesser tendency to induce aggression in humans, Oxazepam is as potent as Chlordiazepoxide for inducing killing by rats. Induction of mouse killing by rats appears to the predict clinical potency rather than the aggressive side-effects of anxiolytic benzodiazepines.     

Chlordiazepoxide and diazepam induced mouse killing by rats

Chlordiazepoxide HCl, at dose levels from 2.5 mg/kg to 80 mg/kg, significantly increased the low base rates of mouse killing (3–9%) observed in large samples (N=100/ dose) of Holtzman strain albino male rats. Maximal killing rates were obtained at doses from 7.5 mg/kg to 20 mg/kg. Diazepam was equally effective, and several times more potent than chlordiazepoxide. Pentobarbital did not increase killing. Killing induced by chlordiazepoxide was blocked by d-amphetamine SO₄, but not by l-amphetamine, at dose levels similar to those that block undrugged killing in this strain (ED₅₀=1.5 mg/kg). Unlike pilocarpine-induced killing, the effects of chlordiazepoxide were not increased or decreased significantly by either peripherally or centrally active anticholinergic drugs, over wide dose ranges of these agents; nor were the effects of chlordiazepoxide increased by repeated daily administration.A preliminary report of the findings described here was made at the Spring 1974 meeting of the American Society for Pharmacology and Experimental Therapeutics (Wnek, Gay, and Leaf, 1974).     

The antinociceptive effect of vaginal stimulation in the rat is reduced by naloxone

Mechanical stimulation of the vagina produces a powerful antinociceptive effect against a variety of noxious stimuli. In rats tested in either the radiant heat tail flick or the warm water tail immersion test the antinociceptive effect of vaginal stimulation was found to be significantly reduced, but not abolished, following the administration of 10 mg/kg of naloxone. These results are in contrast to those of an earlier study in which naloxone was ineffective against the antinociceptive action of vaginal stimulation in a tailshock vocalization paradigm. It therefore appears that the nature of the noxious stimulus used may influence the type of antinociceptive mechanism triggered by vaginal stimulation.     

Blockade of the discriminative effects of morphine in the rat by naltrexone and naloxone

The capacity of the specific narcotic antagonists naltrexone and naloxone to block the discriminative effects produced by morphine in the rat were evaluated using a two-choice, discrete-trial avoidance task. The antagonists produced a dose-dependent and time-dependent blockade of morphine's effects as measured by responding on the morphine-appropriate choice lever. Naltrexone and naloxone were equipotent when given subcutaneously concomitantly with subcutaneously administered morphine. However, when the antagonists were administered orally at 0, 2, 4 or 8 h prior to s.c. morphine, naltrexone was more potent that naloxone at every time point and had a duration of action at least twice that of oral naloxone. The discriminitive effects of the narcotic analgesics morphine and methadone were also compared after oral and subcutaneous administration. Both drugs produced dose-related discriminative effects and were one-tenth as potent by the oral as by the subcutaneous route of administration. These results suggest that the discriminative effects produced by morphine in the rat can provide an animal model for the quantitative evaluation of the narcotic antagonist properties of drugs that might be considered for use in narcotic antagonist maintenance programs for the treatment of narcotic addiction.Predoctoral trainee of the Public Health Service Graduate Pharmacology Training Grant 2T1 GM179. This project represents partial fulfillment of the degree of Doctor of Philosophy at Emory UniversityRecipient of Research Scientist Development Award K02 DA00008     

Oral ethanol self-administration in the rat: effect of naloxone

Rats responding on a two lever concurrent for ethanol and water, were injected with 5, 10, or 20 mg/kg naloxone hydrochloride 30 min prior to a 30 min session. Only the 20 mg/kg dose had any effect, a decrease in responding for ethanol of up to 50% compared to saline control injection sessions. There were no systematic effects upon water responding. An additional study using sucrose and water as the fluid concurrently available failed to find any effects of naloxone on sucrose responding at the same doses. The effect upon ethanol responding was found not to resemble a pattern of extinction, but rather was best described as a general overall reduction in responding. The relation of these findings to the direct involvement of the endogenous opiate system in ethanol reinforcement is discussed.     

The action of morphine and naloxone on acid secretion by the rat isolated stomach

The action of morphine and naloxone on acid secretion by the rat isolated stomach has been studied. Morphine (10^?7 to 10^?4 M) had no effect upon spontaneous acid secretion. Morphine (10^?6 M) did not modify the acid output in response to sub-maximal stimulation by pentagastrin, histamine, bethanechol or isoprenaline. Naloxone (10^?6 M) was without effect on the response to pentagastrin or histamine. Our results suggest that opiate receptors do not modify acid secretion in this preparation.     

Allosteric modulation by leucine-enkephalin of [3H]naloxone binding in rat brain

The interaction of morphine and leucine-enkephalin with the binding site labeled by [3H]naloxone in the presence of sodium was compared. The effect of fixed concentrations of morphine and leucine enkephalin on the saturation binding of [3H]naloxone demonstrated that whereas morphine was a competitive inhibitor, leucine enkephalin caused a dose-dependent masking of binding sites. From these data we conclude that the enkephalin receptor is allosterically coupled to the morphine receptor.     

Time course of antagonism of morphine antinociception by intracerebroventricularly administered naloxone in the rat

This kinetic profile and half-life of naloxone were studied for possible use in determination of pA₂ and K_B in vivo. Rats were given morphine subcutaneously and after 15 min naloxone or saline, intracerebroventricularly. A further 15 min later, and at 15 min intervals up to 135 min after morphine, the animals were tested for analgesia in the tail flick test. The dose-response curves of the naloxone group were shifted to the right of those for the saline group. Theamount of displacement decreased with time, indicative of the disappearance of naloxone. The graph of log (dose ratio-1) vs. time was linear with negative slope, in agreement with the time-dependent form of the equation for competitive antagonism. From this slope, the half-life of naloxone was calculated to be 13.3 min. These results demonstrate that the time-dependent method is useful in obtaining the kinetics of centrally acting opiate antagonists.     

纳洛酮对离体大鼠心脏缺血再灌流损伤的保护作用

本实验采用离体大鼠心脏Langendorff灌流装置.使心脏停灌(旷置)40 min后再恢复灌流30min.夏制心肌缺血再灌流损伤.观察了纳洛酮对再灌流后冠脉流出液中乳酸脱氢酶(LOH)活性,心肌细胞内钙含量.心肌脂质过氧化产物——丙二醛(MDA)含量和超氧化物歧化酶(SOD)活力变化的影响。结果表明.再灌流后应用纳洛酮能显著减少心肌LDH的释放量.心肌细胞内钙聚集、心肌MDA的生成量及SOD活力降低的程度.提示纳洛酮对缺血再灌流心肌具有保护作用。     

Comparison of subcutaneous and spinal subarachnoid injections of morphine and naloxone on analgesic tests in the rat

Small catheters were chronically implanted subdurally in the rat so that repeated microinjections could be made into the subarachnoid space at the lumbar area. Morphine, injected intrathecally (i.th.) produced analgesia as measured by the tail-flick test at doses $\text{1}\text{100}$ of those by the subcutaneous (s.c.) route. Analgesia from i.th. morphine was reversed by either i.th. or s.c. injected naloxone. The dose of naloxone by the i.th. route was about $\text{1}\text{30}$ of that by the s.c. route. However, i.th. injection was no more effective than s.c. injection of naloxone in reversing analgesia produced by s.c. injection of morphine. When [³H]-labelled naloxone was injected s.c. or i.th. in the above experiment of morphine antagonism, there was a more rapid entry of the labelled material in the brain by the i.th. route of administration. The results raise questions on the relative importance of the spinal mechanism of analgesia produced by s.c. injections of morphine. Analgesia was also measured by the tail-shock vocalization test in which morphine producd a dose-dependent elevation of shock threshold at s.c. doses above those prolonging tail-flick latencies. Morphine injected i.th. at doses above those which elevated tail-flick latency produced hypersensitivity, hyper-reflexia, and convulsive seizure of the hindquarters. The spinal analgesic effect of morphine, when administered localy, appears to have a low ceiling of efficacy.     

Morphine and naloxone effects on tonic immobility and the dorsal immobility response in the rat

Adult male Wistar rats treated with morphine sulfate (0.5, 5.0, and 10.0 mg/kg, SC) showed a dose-dependent potentiation of tonic immobility (TI) and dorsal immobility response (DIR) durations. Naloxone (4.0 mg/kg, SC) did not affect the DIR durations but reversed the potentiated morphine effects on both TI and DIR. These results suggest that although opiate receptors may be involved, mu-opiate receptor function is not essential for modulating various complex immobility responses.     

Effect of intracerebroventricular administration of morphine upon intestinal motility in rat and its antagonism with naloxone

Morphine, intracerebroventricularly (i.c.v.) or intraperitoneally (i.p.) administered to rats, inhibited intestinal propulsion as tested by a charcoal meal. Such an inhibition was shown to be linearly related to the log of administered doses for both routes of administration and the two linear regressions are parallel, so that morphine was calculated to be 206 times more potent when administered i.c.v. than i.p. A dose of morphine fully active by the i.c.v. route was completely inactive when injected by the i.v., i.p., i.m. and s.c. routes. Naloxone, administered i.c.v., blocked the antipropulsive effect of morphine i.c.v. or i.p. The pA2 of naloxone versus morphine, both administered i.c.v. was determined and calculated to be 7.14 (6.76-7.62).     

Interval-dependent inhibition of morphine sensitization of ambulation in mice by post-morphine treatment with naloxone or restraint

The ambulation-increasing effect of morphine (10 mg/kg SC) persisted for approximately 3 h with a peak effect at around 1 h after the administration. This was examined on four occasions at 3-day intervals. Thus, treatment regimen-induced sensitization and the 3-h overall activity in the fourth administration was about 1.7 times higher than that in the first administration. Post-morphine treatments with naloxone (1 mg/kg SC) at 0 (i.e., simultaneously with) to 30 min after each morphine administration almost completely inhibited the induction of morphine sensitization. However, post-morphine treatments with naloxone at 1 h and later had no such inhibitory effect. Similarly, physical restriction of the ambulation of mice for 3 h (restraint), by putting them in a jar (6 cm in diameter, and 15 cm in height) inhibited the induction of morphine sensitization when restrain was started 0–30 min after each administration of morphine. Restraint starting 1 h and later did not alter the morphine sensitization. Post-morphine treatment with saline at any times did not change morphine sensitization. Furthermore, repeated administration of saline alone, naloxone alone, and saline with naloxone post-treatment or restraint did not change the sensitivity to morphine. These results clearly indicate that free ambulation for at least 1 h after the administration of morphine, i.e., the latency to reach the peak effect, is required completely to induce sensitization to morphine in terms of ambulation in mice.     

Effects of humoral modulators and naloxone on morphine-induced changes in the spontaneous locomotor activity of the rat

The s.c. administration of 20 mg/kg of morphine-HCl produced a decrease in the spontaneous locomotor activity (SLMA) of rats. The decrease in SLMA was significantly antagonized by p-chlorophenylalanine (p-CPA). When rats pretreated with p-CPA were given 5-hydroxytryptophan before morphine injection, the marked sedative response to morphine was restored, suggesting that the morphine-induced decrease in SLMA of rats may depend on the release of 5-hydroxytryptamine by morphine. By contrast, the s.c. administration of 5 mg/kg of morphine-HCl produced a significant increase in SLMA of rats. The magnitude of the increase was reduced by atropine, scopolamine or -methyl-p-tyrosine. It appears that both adrenergic and cholinergic mechanisms participate in the increase in SLMA of rats induced by morphine. Both the increase in SLMA produced by 5 mg/kg of morphine and the decrease in SLMA induced by 20 mg/kg of morphine were completely antagonized by the s.c. administration of naloxone-HCl, 0.0625 and 0.25 mg/kg, respectively. Thus, it appears that the receptor with which morphine interacts to produce stimulation is chemically identical with or very similar to the receptor with which morphine combines to induce depression. The former receptors, however, are likely to be located on different neurons from the latter.     

Effects of naloxone on heroin-, amphetamine- and caffeine-stimulated locomotor activity in the rat

We investigated the effects of naloxone on the locomotor activating properties of heroin (0.25 mg/kg SC), d-amphetamine (0.25 mg/kg SC) and caffeine (7.5 mg/kg SC). Naloxone eliminated heroin-stimulated locomotion at doses approximately six times lower than those that blocked amphetamine-stimulated locomotion. Caffeine-induced locomotor activation was insensitive to naloxone at all doses tested. These results suggest that central opiate systems are differentially involved in the behavioral activation produced by heroin, amphetamine and caffeine.     

针刺体穴结合纳洛酮治疗眩晕的临床观察

目的：探讨针刺体穴结合纳洛酮治疗椎基底动脉供血不足致眩晕的临床疗效。方法：对照组用纳洛酮2mg,每日1次静脉点滴,10次为1个疗程,治疗组在对照组的基础上,应用毫针针刺风池穴、天柱穴为主,根据伴随症状酌情配伍相关穴位,伴有恶心、呕吐加内关,眩晕严重者加四神聪,针刺每日1次,留针25min,10次为1个疗程,中间休息2～3d,两个疗程后评价治疗结果。结果：治疗组痊愈80例,总有效率为99％,对照组痊愈15例,总有效率为96％。结论：针刺体穴结合纳洛酮治疗眩晕,疗效好,操作简单,值得推广。     

Effects of naloxone and pentazocine on continuous shock-postponement responding by the pigeon

The effects of pentazocine (3–30 mg/kg) and naloxone (3–100 mg/kg) were determined on the treadle-pressing behavior of pigeons under a schedule of shock postponement. Pentazocine increased the mean rate of responding at the 10 mg/kg dose, and greatly increased the mean shock rate at 30 mg/kg. Naloxone increased the mean response rate at all doses tested, without any increases in shock rates.     

Effect of naloxone on the cardiovascular and sympathetic response to hypovolemic hypotension in the rat

Conscious rats were exposed to acute hypovolemic-hypotension by bleeding (5 ml/300 g body weight). Treatment with the opiate antagonist naloxone (7 mg/kg intra-arterial) following hemorrhage resulted in an increase of systolic blood pressure but not heart rate. Changes in plasma catecholamine levels did not differ between control and naloxone-treated animals. From these results we suggest that the ability of naloxone to improve blood pressure after hemorrhage is not due to increased sympatho-adrenomedullary activity.