Methysergide and metergoline reduce morphine analgesia with no effect on the development of tolerance in rats

A single subcutaneous injection of 5 mg/kg metergoline or 10 mg/kg methysergide, two serotonin antagonists, or 1 mg/kg naloxone, significantly reduced the effect of a subcutaneous dose of 3 mg/kg morphine in the tail immersion test in rats. The same drugs and doses were administered concurrently with 10 mg/kg morphine twice daily for 3 days and nociceptive responses were measured 96 h later. Tolerance to the effect of 3 mg/kg morphine was comparable in animals which had received vehicle+morphine or serotonin antagonists+morphine, whereas naloxone completely prevented the development of tolerance. The results argue against a role of serotonin in the development of tolerance to the antinociceptive effect of morphine and suggest it may be possible to dissociate morphine analgesia from tolerance development, at least in the conditions used in the present study.     

Impaired development of tolerance to morphine analgesia in rats with hereditary diabetes insipidus

Recently it was reported that vasopressin facilitates the development of resistance to the analgesic action of morphine. Therefore, the development of tolerance to daily administration of morphine-HCl (10 mg/kg i.p.) was studied in a series of trials on a hot plate using rats with hereditary diabetes insipidus (DI), which lack the ability to synthesize vasopressin. In contrast to heterozygous DI rats, who developed full tolerance after the fifth injection, homozygous DI rats showed a delayed development of tolerance. Substitution of HO-DI rats with either arginine-8-vasopressin (3 g/rat, s.c. daily) or the endocrinologically inert fragment of vasopressin desglycinamide lysine-8-vasopressin (5 g/100 g, s.c. daily) restored the impaired development of tolerance towards normal. The data support the notion that vasopressin is important to the development of tolerance to narcotic analgesics and that its mechanism of action is dissociated from its endocrine effect but rather resembles that of its known influence on memory consolidation.     

The influence of learning on morphine analgesia and tolerance development in rats tested on the hot plate

The influence of learning on the development of tolerance to the analgesic effect of morphine in rats was examined employing the hot plate procedure. A tested-reinforced (Tr) group and its yoked-control, a tested-non-reinforced (Tnr) group, received identical exposure to the testing procedure; the Tr group was reinforced daily for its behavior on the heated plate whereas the Tnr group was reinforced only on the last day of the experiment. Paired statistical comparisons between these two groups on the last day of the experiment revealed that: 1. premorphine control reaction times on the heated plate were significantly lower in Tr than in Tnr animals; and 2. post-morphine increases in reaction time did not differ between Tr and Tnr animals. It was concluded that whereas some learning does occur in this testing procedure, learning does not influence the behavioral tolerance to morphine which develops in this analgesiometric method. An hypothesis which accommodates this behavioral tolerance and a mechanistic scheme is offered.     

The effects of p-chlorophenylalanine on morphine analgesia,tolerance and dependence development in two strains of rats

The effects of p-chlorophenylalanine (p-CPA; 100 mg/kg/day for 3 days) on morphine analgesia and the development of tolerance and physical dependence were investigated in Sprague-Dawley (SD) and Fisher (F) strains of albino rats. Using a modified flinch-jump method to detect changes in reactivity to electric footshock, F strain rats were more reactive to the footshock than SD rats, but showed less relative increase in threshold (analgesia) than SD rats following various doses of morphine. Pretreatment with p-CPA attenuated significantly morphine analgesia in SD, but not F rats. In animals implanted subcutaneously with morphine pellets, p-CPA appeared to delay the development of tolerance to morphine in both strains of rats. Hyperalgesia and loss of body weight resulted from administration of naloxone to pellet-implanted rats and p-CPA pretreatment lessened these withdrawal effects significantly in SD rats only. These results emphasize the importance of strain differences in the study of morphine analgesia and development of tolerance and dependence. Assuming differences in the function of the serotonergic inhibitory system in the two strains of rats, these data provide general support for the involvement of brain 5-HT mechanisms in modulating, if not mediating the effects of morphine.     

瑞舒伐他汀部分恢复吗啡耐受大鼠的吗啡镇痛效能

目的探讨瑞舒伐他汀对吗啡耐受大鼠的吗啡镇痛效能的影响及其相关的分子机制。方法 48只♂SD大鼠随机分成6组(n=8):Ⅰ组为空白对照组;Ⅱ组为吗啡耐受组;Ⅲ组为10 mg.kg-1瑞舒伐他汀对照组;Ⅳ组、Ⅴ组、Ⅵ组分别为0.4、2、10 mg.kg-1瑞舒伐他汀处理组。Ⅱ、Ⅳ、Ⅴ、Ⅵ组皮下注射吗啡10 mg.kg-1,Ⅰ组和Ⅲ组皮下注射生理盐水,每天8∶00和16∶00各1次,连续10 d。d 6起,上午皮下注射前30 min,Ⅰ、Ⅱ组给予生理盐水灌胃,Ⅲ、Ⅳ、Ⅴ、Ⅵ组给予相应剂量的瑞舒伐他汀灌胃,连续5 d。d 6、11,测定大鼠基础热缩足潜伏期(PWTL)后,计算尾静脉注射吗啡30 min时各组大鼠的MPE值。d 11行为学检测后处死大鼠,留取腰5脊髓,比较各组脊髓内细胞外调节蛋白激酶(ERK)、磷酸化细胞外调节蛋白激酶(p-ERK)及星形胶质细胞表面标志物GFAP的表达水平。结果①d 6,6组的基础PWTL无明显差异。与Ⅰ组相比,Ⅱ、Ⅳ、Ⅴ和Ⅵ组MPE值明显降低(P<0.05)。d 11,6组的基础PWTL无差异。与Ⅰ组相比,Ⅱ、Ⅳ组尾静脉注射吗啡后30 min的MPE值明显降低(P<0.05);与Ⅱ组相比,Ⅴ、Ⅵ组的MPE值明显升高(P<0.05)。②d 11,6组大鼠腰5脊髓内总ERK表达水平差异无显著性。与Ⅰ组相比,Ⅱ、Ⅳ组腰5脊髓内p-ERK表达明显升高(P<0.05);与Ⅱ组相比,Ⅲ、Ⅴ、Ⅵ组腰5脊髓内p-ERK表达明显降低(P<0.05)。与Ⅰ组相比,Ⅱ组腰5脊髓内GFAP的荧光强度明显升高(P<0.05);与Ⅱ组相比,Ⅵ组腰5脊髓内GFAP的强度明显降低(P<0.05)。结论瑞舒伐他汀能够部分恢复吗啡耐受大鼠的吗啡镇痛效果,这可能与其抑制脊髓内ERK的磷酸化,减少星形胶质细胞活化有关。     

Influence of antineoplastic drugs on morphine analgesia and on morphine tolerance

The possible influence of cisplatin, methotrexate, adriamycin and vincristine on thermal pain threshold, morphine analgesia and development of morphine tolerance was investigated in mice. In the hot-plate test, the nociceptive threshold was not affected by acute or repeated administration of any of the antineoplastic drugs used. The analgesic activity of morphine was significantly reduced by pretreatment with cisplatin, intraperitoneally (i.p.) injected at the dose of 2 mg/kg. In contrast, methotrexate, subcutaneously (s.c.) injected at the dose of 1 and 5 mg/kg, adriamycin (1 and 3 mg/kg s.c.), vincristine (0.25 and 0.5 mg/kg i.p.) and a lower dose of cisplatin (1 mg/kg i.p.) had no effect. The development of tolerance to morphine analgesia was delayed by adriamycin but was not influenced by the other antineoplastic drugs used. These data show that, of the four antineoplastic agents used in this study, cisplatin may interfere in the mechanism of action of morphine, and that adriamycin may delay the development of opiate tolerance.     

Effects of memantine on estrogen-dependent acute tolerance to the morphine analgesia in female rats

Both human and animal studies suggest that there are sex differences in responding to noxious stimulation as well as in effects of opiate analgesic drugs. Development and/or expression of tolerance to opiate analgesia are also affected by the hormonal status of the experimental subjects. The present study aimed to compare acute tolerance to morphine in cycling and ovariectomized female rats and to evaluate the effects of N-methyl-D-aspartate (NMDA) receptor channel blocker memantine as well as 17-beta-estradiol on tolerance development using the tail-flick test. Acute tolerance to morphine analgesia was observed as a substantial reduction in the response to a test dose of morphine (10 mg/kg) given 6 h after the tolerance-inducing dose (10 mg/kg). Significant acute tolerance was observed in proestrous female rats and was prevented by memantine (3 or 10 mg/kg) treatment. Ovariectomized rats did not demonstrate tolerance to morphine analgesic effects but chronic estradiol administration (5 microg/day, 5 days) reinstated induction of tolerance. Both estrogen receptor modulator tamoxifen (5 mg/kg/day, 5 days) and memantine (3 mg/kg/day, 5 days) prevented estradiol-induced tolerance in ovariectomized rats. Thus, estrogens were found to play a key role in induction of acute tolerance to morphine antinociception. Estradiol-induced acute morphine tolerance may have NMDA receptor-dependent mechanisms.     

Prolactin analgesia: tolerance and cross-tolerance with morphine

The development of acute tolerance to prolactin-induced analgesia in mice was identified by using the writhing test. This tolerance was antagonised by naltrexone pretreatment indicating a role of an opioid mechanism. Cross-tolerance between morphine and prolactin was observed with regard to analgesia. These data show that prolactin mimics morphine properties as far as analgesia is concerned and serve as evidence supporting prolactin-opioid interaction.     

Modification of morphine analgesia and tolerance by flumazenil in male and female rats

This study assessed the effect of the central benzodiazepine receptor antagonist, 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid ethyl ester (flumazenil), on morphine-induced analgesia, locomotor effects, and development of tolerance in rats. The thermally evoked pain (tail flick) response was determined after acute and chronic intraperitoneal (i.p.) administration of morphine and flumazenil, alone and in combination. In acute studies, flumazenil induced weak analgesia unrelated to dose and sex, whereas morphine-induced analgesia was dependent on both dose and sex (male>female). Flumazenil dose-dependently enhanced the analgesic effect of morphine in female but not in male rats. Isobolographic analysis suggested synergism between flumazenil and morphine in female rats, but antagonism in male rats. Flumazenil-induced locomotor changes (alone and with morphine) were related to sex but not dose. Chronic coadministration of flumazenil with morphine enhanced analgesia and attenuated tolerance development in female rats. The findings suggest a possible role for flumazenil as an adjunct with opioids in acute and chronic pain therapy.     

Development of tolerance to the antinociceptive effect of metergoline

Metergoline given IP reduced the response to noxious stimulation in the mouse formalin test. Tolerance to this effect developed after a chronic treatment schedule consisting of ten daily injections of 5 mg/kg. Twenty four hours after the last injection a test dose of metergoline (2.5 mg/kg) reduced the licking time in the formalin test by 28% in the chronic metergoline group, compared to 68% reduction in the vehicle-treated animals. In addition, the antinociceptive effect of the 5-hydroxytryptamine releasing compoundp-chloroamphetamine (PCA) was reduced following chronic treatment with metergoline. The reduced effect of PCA may have been caused by down-regulation of 5-HT₂ receptors. However, this finding is also compatible with the contention that metergoline may act as an agonist at postsynaptic serotonergic receptors.     

Nitroglycerin inhibits the development of morphine tolerance and dependence in rats

The development of tolerance to and physical dependence on opioids remains a significant barrier to their clinical use. N-Methyl-D-aspartate (NMDA) receptor antagonists inhibit tolerance and dependence. However, many NMDA antagonists have undesirable side effects. It has been shown that nitroglycerin (NTG) can antagonize NMDA receptor activity. This study was designed to determine whether NTG could inhibit the development of morphine tolerance and dependence. Rats were anesthetized and implanted with either morphine or placebo pellets, and pumps infusing vehicle or NTG (doses from 0.1 microg/kg/day to 10 mg/kg/day). Tolerance development was assessed by tail-flick latency (TFL). After 6 days, withdrawal was precipitated by subcutaneous injection of 2 mg/kg naloxone. Withdrawal signs were observed for 15 min. Placebo-pelleted rats showed no changes in TFL over the course of the study and no withdrawal signs. Morphine-pelleted rats developed tolerance. The 0.1 mg/kg/day NTG dose significantly attenuated tolerance development, while the other doses had no significant effect. The 0.1 mg/kg/day dose also attenuated some withdrawal signs. Higher or lower doses were not effective, possibly because of competing biochemical effects.     

Enhanced development of morphine tolerance in rats treated with 2-deoxy-d-galactose

Rats treated subcutaneously for 6 days with morphine developed a weak tolerance which was characterized by a decrease in the analgesic action of the opioid. Under those experimental conditions a simultaneous intracerebroventricular application of 2-deoxy-d-galactose enhanced development of morphine tolerance, while other deoxy-sugars like 2-deoxy-d-glucose and 6-deoxy-d-galactose were ineffective. In contrast, no influence of 2-deoxy-d-galactose on a more enhanced morphine tolerance after a 11-day pretreatment with morphine was found. The results are discussed in the light of a rather specific interference of 2-deoxy-d-galactose with neuronal glycoprotein processing and related cellular mechanism underlying adaptive processes involved in the development of morphine tolerance.     

Estrous cycle stage-dependent expression of acute tolerance to morphine analgesia in rats

Both baseline pain sensitivity and the response to antinociceptive treatment are sensitive to an animal's sex and estrous cycle stage. Sex differences are also observed in the development of antinociceptive tolerance induced by repetitive exposure to opiate drugs such as morphine. Conventional tolerance study protocols do not assess the impact of the estrous cycle stage. The present study aimed to compare the development of acute tolerance to morphine-induced antinociception in male and female (cycling and ovariectomized) Wistar rats using the tail-flick test. Acute tolerance was induced by two consecutive subcutaneous injections of morphine (10 mg/kg) or saline separated by an interval of 6 h. It was found that rats pretreated with morphine were tolerant to the second morphine dose. Tolerance was most pronounced in proestrous female rats and, to a lesser degree, in male rats. It was absent in ovariectomized rats as well as during the estrus, metestrus and diestrus phases. Thus, the estrous cycle exerts dramatic effects on the induction of acute tolerance to morphine-induced antinociception. These results suggest that pain management strategies can be optimized through the use of sex- and estrous cycle-specific techniques.     

A pharmacokinetic-pharmacodynamic model of tolerance to morphine analgesia during infusion in rats

A pharmacokinetic-pharmacodynamic (PK-PD) model was constructed to describe the kinetics of tolerance development to morphine-induced antinociception. Tail-flick latencies in response to hot water (50°C) were assessed in male Sprague-Dawley rats exposed to a 12-hr iv infusion of either morphine (1.4 to 3.0 mg/kg per hr) or saline. Morphine-induced antinociception, expressed as the percentage of maximum possible response (%MPR), peaked after 120 min of infusion and decreased thereafter despite sustained systemic morphine concentrations. Both the rate and extent of tolerance development increased with increasing concentrations; an overall residual effect of approximately 24% MPR was observed at the end of the infusion regardless of the steady-state morphine concentration. The kinetics of tolerance offset were examined in a separate experiment by assessing tail-flick latency 15 min after morphine iv bolus (2 mg/kg) in tolerant and control rats. Recovery of response neared completion 18.5 days after a 12-hr exposure to morphine (2.0 mg/kg per hr). A PK-PD model was constructed to account for the delay in onset of antinociceptive effect and tolerance development relative to the blood concentration-time profile. According to this model, both the extent and the rate of tolerance development were modulated by the kinetics of the drug in the central compartment. Accumulation of a hypothetical “inhibitor” acting either as a reverse agonist, a competitive or noncompetitive antagonist, or a partial agonist could potentially account for the loss of pharmacologic effect in the presence of an agonist. The rate of tolerance development predicted from the PK-PD model varied widely (28-fold) depending on the type of pharmacologic interaction selected to account for the loss of effect. Using the rate of tolerance offset to discriminate between the different models (t_1/2 offset 5.4 days), onset and offset of tolerance was described accurately by postulating that the inhibitor behaves as a partial agonist with low intrinsic activity (5.5% MPR) and high binding affinity for the receptor (IC₅₀ 15.0 ng/ml). Presented in part at the Seventh Annual Meeting of the American Association of Pharmaceutical Scientists, San Antonio, Texas, November 15–19, 1992.     

Drug signals enhance morphine tolerance development in hypophysectomized rats

Hypophysectomized and sham-operated (normal) rats were given morphine (5 mg/kg) either paired or unpaired with distinctive environmental cues. Both hypophysectomized and normal animals developed analgesic tolerance when drug effects were signaled, but little tolerance was evident in either surgery group when drug was unsignaled. Results suggest that the pituitary is not critical to associational tolerance development.