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1.
Naloxone reversal of morphine elicited hyperactivity   总被引:1,自引:0,他引:1  
P Schnur  D Hang 《Life sciences》1987,40(4):329-333
When naloxone is administered during morphine elicited hyperactivity, hyperactivity is reversed and hypoactivity occurs in its place. The present experiment tested the hypothesis that this effect is the result of morphine induced supersensitivity to naloxone. Two groups of hamsters received equivalent pretreatment with 15 mg/kg morphine (Groups M/M and M/S) for three days while a third group received saline (Group S/S). During subsequent testing one group received a morphine injection (Group M/M) while the others received saline (Groups M/S and S/S) before being placed in running wheels for a three hour session. Two hours later half the animals in each group received an injection of 0.4 mg/kg naloxone and half received saline. Naloxone produced hypoactivity in animals running under the influence of morphine (Group M/M), but neither in those with an equivalent history of morphine pre-treatment (Group M/S), nor in saline controls (Group S/S). These results are inconsistent with the hypothesis under test, but congruent with a modified dual-action hypothesis.  相似文献   

2.
Male ICR mice were rendered tolerant to and dependent on morphine by subcutaneous implantation of a 75 mg morphine pellet for 72 hours. At 2, 4, and 6 hours after pellet removal groups of 7–10 mice were challenged with ip saline or naloxone and their brain concentrations of morphine estimated by radioimmunoassay (RIA). The brains were prepared for RIA by either organic or inorganic (0.01 N HC1) extraction and in most experiments the two methods were shown to be equivalent with respect to the final concentration of morphine. There was no difference in brain morphine between saline and naloxone (10 mg/kg) treated groups when they were challenged 4 hours after pellet removal and sacrificed 1, 5, 10, 15, 20, 30, 45, and 60 minutes later. In contrast, when the challenge was administered 6 hours after pellet removal the naloxone treated groups has higher concentrations of brain morphine than the saline controls. Brain levels in mice that received 0.10, 1.0, 10, 100 mg/kg naloxone did not differ consistently from saline controls. We found no consistent evidence that naloxone decreases the concentration of morphine in brain homogenates obtained from mice during the initial 6 hours after pellet removal.  相似文献   

3.
A significant enhancement of the analgetic effect of morphine (6 mg/kg, subcutaneously; tail withdrawal reflex at 60 degrees C) was observed in rats 3-4 hours after single naloxone (1 mg/kg) administration. Periodical naloxone injection (0.5 mg/kg, subcutaneously, 3 times per day at 3.5-hour intervals for 3 days) led to a prominent and long-term (testing on the 20th and 105th hour after the last naloxone administration) enhancement of morphine analgesia (2.6 mg/kg subcutaneously) and insignificant inhibition of stress analgesia during two-hour immobilization of animals. These modifications of morphine and stress analgetic effects are considered a result of adaptive changes of opiate receptors after their blockade.  相似文献   

4.
Low doses of morphine (0.30–2.5 mg/kg) decrease in a dose-dependent manner spontaneous climbing behaviour in mice. This effect is not modified by administration of naloxone at doses up to 1.25 mg/kg. These morphine doses do not modify the locomotor activity but, when they are associated with naloxone (0.5 mg/kg), an obvious inhibition occurs. In rats, a hyperactivity follows the akinesia produced by a morphine administration (10 mg/kg). This hyperactivity is changed into a significant hypokinesia when the animals are treated with naloxone (0.05 mg/kg). These results might reveal a dual effect of low doses of morphine, the excitatory effect of morphine being antagonized by naloxone whereas no action on the sedative effect is observed.  相似文献   

5.
2-Diazomorphine-bovine serum albumin (2-DAM-BSA) was prepared by diazotizing p-aminobenzoyl-BSA to morphine. Rabbits immunized with 2-DAM-BSA produced antibodies directed to morphine. A 50 percent reduction in 3H-morphine binding required 4.4 pmol of morphine, and 60, 225, and 350 pmol of normorphine, morphine-3-glucuronide, and codeine, respectively. A radioimmunoassay for brain morphine is described, validated, and used to determine if naloxone alters brain morphine in morphine pelleted mice. The apparent biological half-life of morphine in brain was approximately 52 hours between 24 and 72 hours after pellet implantation, and decreased to 1.25 hours after pellet removal. Naloxone (10 mg/kg) administered 24, 48, or 72 hours after implantation and in doses of 1.0–100 mg/kg administered at 48 hours resulted in either no significant change, or, in a few experiments, increased the brain concentration of morphine. The present experiments could not detect a fraction of total brain morphine that is reduced by naloxone.  相似文献   

6.
1. The antinociceptive effect in the mole-rat of morphine (1, 10, 20 or 30 mg/kg) and nefopam (10 or 20 mg/kg) was studied. 2. In the hotplate test, morphine had no analgesic effect. A reduced response latency after morphine (10 and 20 mg/kg) could possibly be explained by hyperactivity and excited behaviour. 3. After morphine (10, 20 and 30 mg/kg) most of the animals died after fighting when kept in colony cages. Aggressive behaviour and death was prevented by naloxone, or by keeping the animals in single cages. 4. Nefopam (20 mg/kg) significantly increased the latency for the nociceptive response. 5. It was concluded that in the mole-rat, opioid systems in the CNS may not be involved in the regulation of nociception, but in the regulation of agonistic and motor behaviour.  相似文献   

7.
The effects of naloxone pretreatment on opiate agonist-induced depressions in serum luteinizing hormone (LH) levels were examined in male rats. Our results demonstrated a pronounced enhancement of morphine's actions 6 hours after the administration of naloxone (0.5 mg/kg). This effect was characterized by a 10 fold reduction in the ED50 (1.26 mg/kg versus 0.13 mg/kg in saline- and naloxone-pretreated rats, respectively) and much greater depressions in serum LH levels at each dose of morphine. The actions of naloxone were not confined to morphine, since similar increased potencies were found for opioid agonists with selectivity for a variety of opioid receptor subtypes. Because naloxone did not alter the uptake of subsequently administered morphine into brain, our results cannot be explained on the basis of an increased availability of the agonist. Rather, it appears that naloxone pretreatment induces a change in the sensitivity of those receptors involved in the effects of opioid agonists on LH.  相似文献   

8.
In unanesthetized rats, naloxone (5 mg/kg, s.c.) produced an increase in both respiratory frequency and tidal volume as compared to saline administered animals. Maximal respiratory stimulation was observed within 5 minutes after naloxone injection and duration of the response was greater than 30 minutes. Exposure to different atmospheres of carbon dioxide potentiated the increase in ventilation in a step-wise manner as the carbon dioxide concentration was increased. Pretreatment with low doses of morphine sulfate (2 mg/kg daily for 2 days) or naloxone HCl (5 mg/kg daily for 5 days) enhanced respiratory stimulation induced by naloxone. It was concluded that naloxone increases the sensitivity of central ventilatory response to carbon dioxide as a result of displacement of endogenous endorphins from central opioid receptors.  相似文献   

9.
Systemically administered beta-endorphin was tested in rats for its ability to modify the hypothermia and hypermotility induced by d-amphetamine. Colonic temperature and motor activity were measured in a cold (4°C) ambient temperature in animals given IP injections of beta-endorphin (0.1, 1.0, or 3.0 mg/kg), naloxone (10 mg/kg), or morphine (30 mg/kg). The same measurements were taken in animals given beta-endorphin (1.0 mg/kg) in combination with naloxone or saline pretreatment and d-amphetamine (15 mg/kg) or saline post-treatment. Morphine alone had a biphasic effect on thermoregulation, but did not affect d-amphetamine-induced hypothermia. Activity scores were decreased by morphine, in both d-amphetamine and saline treated animals. The thermal response of rats to beta-endorphin alone was variable, depending on dosage, but all 3 dosages partially blocked the hypothermic effect of d-amphetamine. Naloxone blocked the thermal effects of both beta-endorphin and d-amphetamine. Motor activity tended to be decreased by naloxone, regardless of amphetamine treatment, but beta-endorphin tended to increase activity in amphetamine-treated animals and reduce it in saline-treated controls. In their actions on both thermoregulation and activity, naloxone and beta-endorphin appeared to interact independently with d-amphetamine, often producing effects in the same direction, but in combination, they tended to be mutually inhibitory.  相似文献   

10.
L.J. King  K.H. Minnema  C. Cash 《Life sciences》1977,21(10):1465-1473
Morphine sulphate (4 mg/kg to 32 mg/kg) produced a dose-dependent decrease in brain malate as antinociception increased. Decreased brain malate persisted 72 hours after implantation of morphine pellets by which time mice had become tolerant to antinociception. This finding suggests that malate decrease, unlike changes of other metabolites in other studies, might not be simply a result of general metabolic changes. Malate change as well as antinociception was prevented by prior injection of naloxone (3.0 mg/kg) or naltrexone (0.6 mg/kg) in acute experiments. Malate decrease in pelleted mice was no longer present if withdrawal was produced by naloxone or naltrexone in mice implanted with morphine pellets for 72 hours. Brain P-creatine was elevated in all mice implanted with morphine pellets even after withdrawal, thus, apparently, representing a more generalized effect than malate change.  相似文献   

11.
The present investigation examined the neural sites and mechanisms of opiate inhibition of female sexual behavior. Systemic administration of morphine (10 mg/kg) significantly reduced ovarian steroid-induced estrous behavior in female rats. This behavioral inhibition was prevented when the opiate receptor antagonist naloxone (5 mg/kg) was administered 30 min prior to morphine. Bilateral infusion of morphine directly into the ventromedial hypothalamus (VMH) also inhibited hormone-dependent estrous behavior for at least 2 hr. Furthermore, naloxone infusion into the VMH 20 min before behavior testing reduced the inhibitory effects of systemically administered morphine on lordosis. These results suggest that morphine may inhibit female sexual behavior by acting directly on the VMH, the primary site at which ovarian steroids facilitate this behavior. In a separate experiment we used in vivo brain microdialysis to test the hypothesis that morphine inhibits lordosis by interfering with norepinephrine (NE) neurotransmission in the VMH. In control rats, the onset of mating was associated with increased NE release in the VMH. Morphine-treated animals displayed neither behavioral estrus nor elevated NE release from the VMH when tested with stimulus males. These data are consistent with the hypothesis that morphine suppresses NE release in the VMH. Nevertheless, mechanisms other than or in addition to attenuation of hypothalamic NE release may contribute to the inhibitory effects of morphine on lordosis.  相似文献   

12.
Coupar IM  Tran BL 《Life sciences》2001,69(7):779-790
The aim of this study was to investigate whether the A1/A2 receptor agonist, 5'-N-ethylcarboxamidoadenosine (NECA), and the selective A1 agonist, N6-cyclopentyladenosine (CPA), induced physical dependence by quantifying specific antagonist-precipitated withdrawal syndromes in conscious rats. In addition, the presence of bidirectional cross-withdrawal was also investigated. The agonists were administered s.c. to groups of rats at 12 h intervals. Antagonists were administered s.c., 12 hours after the last dose, followed by observation and measurement of faecal output for 20 min. NECA (4 x 0.03 mg kg(-1), s.c) and CPA (4 x 0.03, 0.1 and 0.3 mg kg(-1), s.c.) induced physical dependence, as shown by the expression of a significant withdrawal syndrome when challenged with the adenosine A1/A2 receptor antagonist, 3,7-dimethyl-1-propargylxanthine (DMPX, 0.1 mg kg(-1), s.c.) and the A1 antagonist, 8-cyclopentyl-1,3-dipropylxanthine (CPDPX, 0.1 mg kg(-1), s.c.) respectively. The syndromes consisted of teeth chattering and shaking behaviours shown to occur in morphine-dependent animals withdrawn with naloxone viz, paw, body and 'wet-dog' shakes, but with the additional behaviours of head shaking and yawning. In further contrast to the opiate withdrawal syndrome, no diarrhoea occurred in the groups of animals treated with adenosine agonists and withdrawn with their respective antagonists. Bidirectional cross-withdrawal syndromes were also revealed when naloxone (3 mg kg(-1), s.c.) was administered to adenosine agonist pre-treated rats and adenosine antagonists were given to morphine pre-treated rats. This study provides further information illustrating that close links exist between the adenosine and opiate systems.  相似文献   

13.
G A Higgins  P Nguyen  E M Sellers 《Life sciences》1992,50(21):PL167-PL172
The non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist dizocilpine has recently been reported to antagonize certain overt withdrawal signs in morphine dependent rats. The purpose of the present study was to reassess this response and examine the effect of this drug in a model presumably reflective of the motivational impact of withdrawal using the place conditioning technique. Rats were made opiate dependent by the subcutaneous implantation of a 75 mg morphine pellet. Three-4 days later withdrawal was precipitated by naloxone 0.5 mg/kg. Dizocilpine (0.1-0.5 mg/kg) attenuated many of the subsequent behaviours elicited by naloxone, notably diarrhoea, mouth movements, paw shakes and ptosis. In a separate group of morphine dependent rats, naloxone (0.05 mg/kg) precipitated withdrawal produced a clear place aversion. This place aversion was blocked by dizocilpine (0.02-0.1 mg/kg) pre-treatment prior to conditioning. Therefore dizocilpine may modify both motivational and somatic aspects of opioid withdrawal.  相似文献   

14.
Heart rate (HR) and mean arterial blood pressure (BP) were recorded from conscious, chair-restrained squirrel monkeys surgically prepared with chronically indwelling arterial and venous catheters to determine the effects of acute intravenous injections of two opiate antagonists and an agonist. Naloxone (0.3–10.0 mg/kg) or naltrexone (0.3–10.0 mg/kg) had little effect on HR or BP during a 30-minute post-injection period. Morphine (3.0–5.6 mg/kg) produced biphasic effects comprising an initial decrease followed by an increase in HR, and an increase followed by a decrease in BP. Lower morphine doses had lesser effects during a 100-minute post-injection period. Pre-treatment with 0.03 mg/kg naloxone attenuated the depressive effect of morphine on HR and BP, but increases in HR and BP due to morphine were enhanced. Pretreatment with 0.3 mg/kg naloxone prevented morphine-induced decreases in HR and BP, yet increases in HR and BP persisted. In previous behavioral studies, morphine in combination with naloxone similarly increased rates of responding in the squirrel monkey. Together, these data suggest an effect of naloxone that goes beyond mere pharmacological antagonism of the effects of morphine.  相似文献   

15.
《Life sciences》1995,58(4):PL55-PL61
The behavioral effects of MK-801 were compared in morphine-dependent and non-dependent mice. The dose of MK-801 selected for these studies was previously demonstrated to attenuate some of the morphine withdrawal signs. Subjects were repeatedly exposed to morphine (8 days, b.i.d., 10–100 mg/kg, s.c.). Twenty-four hours after last morphine injection mice received naloxone (0.1 mg/kg, s.c.) and the observation was commenced. Animals were pretreated with either MK-801 (0.1 mg/kg, i.p.) or saline 30 min prior to testing. It was found that the behavioral effects of MK-801 (decreased sociability and increased rate of transitions between behavioral elements, locomotion, grooming) were less pronounced in morphine-dependent compared to non-dependent subjects. However, the intensified almost stereotypic eating possibly reflected increased psychotomimetic potency of MK-801 in morphine-withdrawn animals.  相似文献   

16.
Administration of naloxazone (50 mg/kg i.v.), an irreversible, selective and long acting antagonist of the μ1 subclass of the opioid receptors, strongly reduced stimulation of PRL secretion by morphine (5.0 mg/kg i.v.) injected 24 hours later into conscious, unrestrained rats. In contrast, the effect of morphine on PRL release was unimpaired in rats treated 24 hours beforehand with either the reversible opioid antagonist naloxone (50 mg/kg i.v.), or the vehicle for naloxazone. A complete suppression of the PRL response to morphine (3.0 mg/kg i.v.) was observed in animals given intraventricular (IVT) injection of β-funaltrexamine (β-FNA, 2.5 μg), another selective, irreversible and long acting antagonist of the μ receptors, 24 hours beforehand. Neither naloxazone nor β-FNA had any effect on the activation of GH secretion by morphine, which, however, was conspiciously reduced by ICI 154, 129, a preferential δ receptor antagonist, injected IVT (50 μg) 5 minutes before morphine. It is concluded that the PRL stimulating effect of morphine is mediated by the μ receptors, wherease activation of GH probably involves the δ sites.  相似文献   

17.
Parity-associated reductions in behavioral sensitivity to opiates   总被引:5,自引:0,他引:5  
Behavioral and physiological responses differ between primiparous and multiparous female rodents. Specifically, multiparous females respond with the full repertoire of maternal behaviors much more rapidly and with greater intensity than their primiparous counterparts. Since opiates inhibit the expression of maternal behavior in postpartum rats and can be reversed by means of the opiate antagonist naloxone, we investigated whether multiparous females would be resistant to the inhibitory effects of opiates on maternal behavior, relative to primiparous females. In Experiment 1 we evaluated the effects of a range of doses of morphine sulfate (MS; 0.625, 1.25, 2.5, 5.0, and 10.0 mg/kg or saline) on maternal behavior in primiparous females on Days 5-6 of lactation. The 5.0 and 10.0 mg/kg doses effectively disrupted maternal behavior, whereas the lower doses were ineffective or only marginally disruptive. In Experiment 2, age-matched female rats were timed-mated and tested for maternal behavior from Day 5 to 13 of lactation, after daily injections of the 5.0 mg/kg dose of MS. On Day 5 of lactation, this morphine treatment eliminated full maternal behavior in 87% of the primiparous animals, but only 37% of the multiparous animals were affected. By Day 10 of lactation, 100% of the multiparous females displayed full maternal behavior after MS treatment, whereas only 69% of primiparous females were responsive. In Experiment 3, analgesic responses were measured both in rats experiencing their initial or second pregnancy, and in postpartum, lactating rats after MS (5.0 mg/kg) administration. Using a tail-flick apparatus to measure analgesia, we found multigravid females to be significantly less analgesic prepartum than primigravid females, suggesting less sensitivity to endogenous opioids.(ABSTRACT TRUNCATED AT 250 WORDS)  相似文献   

18.
Male rats, each implanted with a pellet containing 75 mg morphine, were administered naloxone 72 hours later to precipitate abstinence. Two hours before naloxone, animals were pretreated acutely with either 10 mg/kg cannabidiol (CBD) or the vehicle. One hour later, an injection of the vehicle or a low dose of Δ9-THC that we have shown to exhibit slight efficacy in attenuating morphine abstinence signs was administered to each of the groups previously receiving the vehicle or CBD. Interactions between CBD and Δ9-THC were assessed during abstinence, precipitated one hour after the last series of injections. CBD had little effect on abstinence scores, but significantly increased the abstinence attenuating properties of Δ9-THC, Rotational behavior (turning), induced by Δ9-THC during abstinence, was also potentiated by CBD. These data extend previous reports of potentiation of pharmacological effects of THC by CBD to abstinence-attenuating properties and other effects of THC in morphine-dependent rats.  相似文献   

19.
Chronic administration for 16 days of haloperidol (in increasing doses up to 20 mg/kg/day) results in a supersensitivity of dopamine receptors. This supersensitivity is manifested by an enhanced stereotypy and aggression in response to small, otherwise ineffective, doses of apomorphine. Maximum aggression is observed 7 days after the last dose of haloperidol when 2.5 mg/Kg of apomorphine is administered. In addition, “wet shakes”, reminiscent of withdrawal from morphine, are observed in these animals after the cessation of the haloperidol administration. These shakes are blocked by morphine. These results may be interpreted to mean that “wet shakes” and drug induced aggression are the results of hyperactivity of the dopaminergic system.  相似文献   

20.
A Bianchetti  A Guidice  F Nava  L Manara 《Life sciences》1986,39(24):2297-2303
Mice were rendered physically dependent by repeated administration of morphine, 25 mg/kg s.c., 5 times daily for 4 days, and on the 5th day, 2 h after the last morphine dose, they were challenged with a s.c. injection of either naloxone, 25 mg/kg, or the peripherally selective opioid antagonist SR 58002 C (N-methyl levallorphan mesilate), 75 mg/kg. Naloxone provoked jumping and diarrhea in all the animals; mice challenged with SR 58002 C presented no significant jumping but a high frequency of withdrawal diarrhea. When naloxone, 12 mg/kg, or SR 58002 C, 50 mg/kg, were given s.c. in combination with repeated morphine as above, mice which had received naloxone with morphine presented virtually no diarrhea or jumping upon naloxone challenge; those repeatedly treated with morphine plus SR 58002 C were substantially protected from naloxone-precipitated diarrhea, but not jumping. These results further support the remarkable selectivity for peripheral opioid receptors of SR 58002 C, even after repeated high-dose treatment, and are strongly consistent with the primary role of a local intestinal mechanism in the development and expression of opioid withdrawal diarrhea in mice. The in vivo dissociation of central and peripheral components of dependence on morphine is illustrated, apparently for the first time.  相似文献   

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