Tolerance to and cross tolerance between ethanol and nicotine

Female DBA mice were subjected to one of four treatments: ethanol-containing or control diets, nicotine (0.2, 1.0, 5.0 mg/kg/hr) infusion or saline infusion. After removal from the liquid diets or cessation of infusion, the animals were challenged with an acute dose of ethanol or nicotine. Chronic ethanol-fed mice were tolerant to the effects of ethanol on body temperature and open field activity and were cross tolerant to the effects of nicotine on body temperature and heart rate. Nicotine infused animals were tolerant to the effects of nicotine on body temperature and rotarod performance and were cross tolerant to the effects of ethanol on body temperature. Ethanol-induced sleep time was decreased in chronic ethanol- but not chronic nicotine-treated mice. Chronic drug treatment did not alter the elimination rate of either drug. Chronic ethanol treatment did not alter the number or affinity of brain nicotinic receptors whereas chronic nicotine treatment elicited an increase in the number of [3H]-nicotine binding sites. Tolerance and cross tolerance between ethanol and nicotine is discussed in terms of potential effects on desensitization of brain nicotinic receptors.     

Bidirectional contingent cross tolerance between the anticonvulsant effects of pentobarbital and ethanol.

In Experiment 1, two groups of kindled rats received a pentobarbital injection (15 mg/kg, IP) and a convulsive amygdala stimulation once every 48 h. In one group, pentobarbital was injected 1 h before each stimulation; in the other, it was injected 1 h after each stimulation. Only the rats that received pentobarbital before each stimulation became tolerant to pentobarbital's anticonvulsant effect. Cross tolerance to the anticonvulsant effect of ethanol (1.5 g/kg, IP) was also found to be greater in the pentobarbital-before-stimulation rats. Experiment 2 was designed to assess the transfer of tolerance in the opposite direction, that is, from ethanol to pentobarbital, and the results mirrored those of Experiment 1: convulsive stimulation during the periods of ethanol exposure facilitated the development of tolerance to the anticonvulsant effect of ethanol and its transfer to pentobarbital. These results support the theory that functional drug tolerance and cross tolerance are adaptations to the effects of drugs on concurrent patterns of neural activity rather than to drug exposure per se.     

Tolerance to electroacupuncture and its cross tolerance to morphine

Electroacupuncture (EA) applied to both legs of the rat for 30 min (1session) raised the average tail flick latency to 89% above the control level. Repeated electroacupuncture for 6 sessions, with 30 min between successive sessions, resulted in a gradual decline in the hypoalgesic effect. The time-course of the development and disappearance of acupuncture tolerance was studied. A bidirectional cross-tolerance between electroacupuncture and morphine points to the similarity between the underlying mechanisms of electroacupuncture hypoalgesia and morphine analgesia.     

The development of tolerance to morphine in the rat

Tolerance to various effects of morphine in the rat can be quantified by means of a shift of semilogarithmic dose-response curves. Tolerance to analgesia (hot plate, acetic acid writhing), catalepsy, and the tilted plane develops in a closely similar manner. Also, the stimulating effects of about 1 mg/kg morphine-HCl tested in an open-field procedure are somewhat less pronounced in chronically treated rats than in naive ones. There is no correlation between tolerance development and the acute ED₅₀ of different tests.     

Learned and pharmacologically-induced tolerance to ethanol and cross-tolerance to morphine and clonidine

The development of tolerance to the inhibitory effect of ethanol on the tail-flick reflex was studied in the spinal rat. This preparation was used in order to avoid uncontrolled learning effects. Tolerance due to intoxicated practice (learned tolerance) and tolerance due to mere ethanol exposure (pharmacologically-induced tolerance) were studied in separate experiments. It was found that that learned tolerance to ethanol also caused tolerance to morphine and clonidine, whereas pharmacologically-induced tolerance did not have the same effect. The results challenge the concept of "behaviorally augmented tolerance" and suggest that learned and pharmacologically-induced tolerance involve different basal mechanisms in the CNS.     

The rapid development of functional tolerance to ethanol by mice

A method is described in which the development of tolerance to ethanol in individual mice can be measured during the inhalation of ethanol vapour. This method has been used with two behavioural end-points, loss of righting reflex and loss of rotarod performance. It demonstrates that, in the adult male, TO Swiss mouse, peak tolerance, in which approximately 2 × the original effective blood ethanol concentration is required to produce the behavioural end-point, can develop in 3–5 h. After this time the ability of the animals to perform normally in the presence of continued high concentrations of ethanol in blood begins to fall. The results are discussed in relation to current concepts of tolerance to central nervous system depressant drugs.     

The development of morphine antinociceptive tolerance in nitric oxide synthase-deficient mice

Elevations in nitric oxide (NO) have been implicated in the development of morphine antinociceptive tolerance. This study was conducted to establish the role of specific isoforms of NO synthase (NOS) in morphine tolerance development using genetically modified mice. METHODS: Three groups of mice (endothelial NOS [eNOS]-deficient, neuronal NOS [nNOS]-deficient, and NOS-competent) were used in this experiment. On Day 1, the analgesic response (radiant heat tail-flick) to a challenge dose of morphine (4 mg/kg) was determined over 3 hr. Tolerance was induced on Days 1-5 by administering morphine subcutaneously (10 mg/kg) or L-arginine, a NO precursor, intraperitoneally (200 mg/kg), twice daily. Analgesic response to the challenge dose was determined again on Day 6. RESULTS: Following sustained morphine administration, nNOS-deficient mice exhibited less tolerance development when compared to the control group, although measurable tolerance still occurred. Mice deficient in eNOS evidenced a degree of tolerance similar to that of control. Prolonged L-arginine administration produced significant functional tolerance to morphine in NOS-competent and eNOS-deficient mice. The loss of morphine responsivity after L-arginine administration was similar to that after morphine pretreatment. L-Arginine did not affect the antinociceptive response to morphine in mice deficient in nNOS, suggesting that the small degree of morphine-induced tolerance in this group occurs through an alternate pathway. CONCLUSIONS: These data demonstrate the pivotal role of the neuronal isoform of NOS in development of morphine antinociceptive tolerance. Furthermore, tolerance development appears to be predominantly a NO-mediated process, but likely is augmented by a secondary (non-NO) pathway.     

The stimulus properties of morphine and ethanol

The present investigation sought (a) to establish the efficacy of morphine and ethanol as discriminative stimuli when each is paired with the administration of saline and (b) to compare, in a qualitative sense, the stimulus properties of the two drugs. Additional experiments examined the effects of treatment with naloxone or l-propranolol upon morphine and ethanol-mediated discriminated responding. Finally, the stereospecificity of the stimuli produced by morphine was determined by a comparison, in morphine-trained rats, of levorphanol and dextrorphan. Discriminated responding developed rapidly in both the morphine and ethanol groups. In tests in which ethanol was administered to morphine-trained animals and vice versa, no similarity to stimulus properties was apparent. Antagonism of discriminated responding induced by morphine and ethanol was attempted using naloxone and l-propranolol. Naloxone blocked the actions of morphine but was without effect upon ethanol. No evidence of antagonism of either drug by propranolol was found. When a range of doses of levorphanol (0.1–3 mg/kg) and dextrorphan (3–100 mg/kg) was tested in morphine trained animals, only levorphanol was able to substitute for morphine. The present results suggest that the stimulus properties of morphine represent typical opiate effects.     

Cross-tolerance between morphine and ethanol and their antinociceptive effects

Morphinization of mice (37.5 mg morphine) and rats (75 mg) with subcutaneously implanted pellets has resulted in tolerance to the antinociceptive effect of morphine, measured in the tail-immersion test. All animals also developed cross-tolerance to the analgesic effects of ethanol (2.8 g/kg intraperitoneally for mice, per os for rats). These results suggest a commonality between morphine and ethanol antinociceptive action.     

Adrenergic function and the development of analgesic tolerance to morphine

Whether or not the suppressive effect of alpha- and beta-adrenergic blockers, phentolamine and propranolol, on the development of tolerance to morphine could be substituted for each other was investigated in mice. Daily co-administration of either one of the blockers with morphine suppressed the development of analgesic tolerance to morphine as far as the treatment was continued without affecting the analgesic effect per se; however, the suppressive effect was lost from the day of the substitution for the other blocker and tolerance developed as rapidly as in the control group treated with morphine alone. Co-administration of both blockers with morphine also maintained the analgesic effect on the 1st day for 10 days, but when the administration of either one or both blockers was eliminated from the 6th day, the development of tolerance was initiated. These results suggest that the mechanisms of alpha- and beta-blockers for the suppression of the development of analgesic tolerance to morphine are different from each other and that adrenergic blockers may produce a specific alteration in the mechanism for the development of tolerance to morphine.     

The rapid development of functional tolerance to ethanol by mice.

A method is described in which the development of tolerance to ethanol in individual mice can be measured during the inhalation of ethanol vapour. This method has been used with two behavioural end-points, loss of righting reflex and loss of rotarod performance. It demonstrates that, in the adult male, TO Swiss mouse, peak tolerance, in which approximately 2 X the original effective blood ethanol concentration is required to produce the behavioural end-point, can develop in 3--5 h. After this time the ability of the animals to perform normally in the presence of continued high concentrations of ethanol in blood begins to fall. The results are discussed in relation to current concepts of tolerance to central nervous system depressant drugs.     

Effect of a calcium chelator on morphine tolerance development

To assess the effects of calcium ion chelation on narcotic tolerance development, adult Sprague-Dawley rats were implanted with i.c.v. cannulae connected to osmotic minipumps for continuous infusions of saline or EGTA (2 mumol/24 h) during chronic morphinization by s.c. pellet implantation. Additional rats receiving the same morphine pellet treatment but without minipumps served as non-surgical controls. After 64 h the minipumps and pellets were removed and narcotic tolerance was assessed by the tail-flick technique. A positive analgetic response to an 8.50 mg/kg s.c. dose of morphine sulfate was noted in 6/12 no-minipump controls and 4/9 saline-infused controls. In placebo-treated rats caused no alteration of either baseline tail-flick latencies or in analgetic responsiveness to lower doses of morphine. It is concluded that the enhancement of morphine tolerance by EGTA (a calcium-specific chelator) results from a facilitation of certain adaptive changes of calcium ion disposition that are related to the neurochemical mechanisms of narcotic tolerance and dependence development.     

吗啡耐受及内脏痛敏的相关机理

目的　吗啡耐受是一种潜在的痛觉过敏 ,慢性内脏炎痛刺激后也产生内脏痛敏。因此探讨慢性内脏炎痛刺激及吗啡耐受间共同的细胞机理及N 甲基 D 天冬氨酸 (NMDA)受体相关的调节机理 ,为合理用药及药物开发提供实验依据。方法　利用急慢性内脏痛炎痛模型 ,直肠扩张痛阈测定及生物化学检测的方法进行机理研究。结果　结肠炎症和慢性吗啡耐受的大鼠均出现直肠扩张痛阈降低 ,即内脏痛敏现象 ,而慢性地佐环平 (MK 80 1)和L NG 硝基精氨酸甲酯 (L NAME)处理吗啡组的平均痛阈末见明显改变。内脏炎痛和耐受组大鼠脊髓及海马部位一氧化氮合酶 (NOS)上调 ,而MK 80 1和L NAME预处理组含量无明显变化。慢性内脏炎痛及吗啡耐受组背角神经元 [Ca2 + ]i 显著增高 ,而MK 80 1预处理的炎痛及耐受组则无明显改变。结论　吗啡耐受和痛觉敏感化在机理上存在某些共同之处 ,均在NMDA受体的激活、一氧化氮生成及细胞内钙上发生可塑性变化。