Quantitative assessment of tolerance to and dependence on morphine in mice

Summary The actions of 3,4-diaminopyridine, 4-aminopyridine and tetraethylammonium were studied on the chick biventer cervicis muscle preparation. All three compounds produced a greater augmentation of indirectly elicited twitches than of directly elicited twitches. The compounds did not restore transmission in OmMCa²⁺ solutions but rather produced contractures that were inhibited by acetylcholine receptor antagonists. The compounds restored twitch height in one-tenth normal Ca²⁺ solutions and induced spontaneous muscle twitching. The compounds reversed dantrolene-induced block of directly elicited twitches.Interactions between tetraethylammonium and 3,4-diaminopyridine were also studied. In indirectly stimulated preparations, the combined effects of the two compounds were more than additive at one concentration level only. In directly stimulated preparations, the effects of 3,4-diaminopyridine were greatly enhanced by tetraethylammonium pretreatment. 3,4-Diaminopyridine pretreatment produced less synergism than tetraethylammonium pretreatment.It is concluded that the actions of the aminopyridines and tetraethylammonium on transmitter release and muscle contractility are essentially similar. These actions are postulated to arise from an inhibitory action on potassium conductance and on ability to release calcium from nerve and muscle membranes. On the basis of the interaction studies, it is suggested that the compounds possess different binding capacities for two different sites on the potassium conducting channel.     

Attenuation of morphine tolerance and dependence by aminoguanidine in mice

The effect of aminoguanidine, an inducible nitric oxide synthase (iNOS) inhibitor, on morphine-induced tolerance and dependence in mice was investigated in this study. Acute administration of aminoguanidine (20 mg/kg, p.o.) did not affect the antinociceptive effect of morphine (10 mg/kg, s.c.) as measured by the hot plate test. Repeated administration of aminoguanidine along with morphine attenuated the development of tolerance to the antinociceptive effect of morphine. Also, the development of morphine dependence as assessed by naloxone-precipitated withdrawal manifestations was reduced by co-administration of aminoguanidine. The effect of aminoguanidine on naloxone-precipitated withdrawal was enhanced by concurrent administration of the non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist, dizocilpine (0.25 mg/kg, i.p.) or the non-specific nitric oxide synthase (NOS) inhibitor, l-N(G)-nitroarginine methyl ester (l-NAME; 5 mg/kg, i.p.) and antagonized by concurrent administration of the nitric oxide (NO) precursor, l-arginine (50 mg/kg, p.o.). Concomitantly, the progressive increase in NO production, but not in brain glutamate level, induced by morphine was inhibited by repeated administration of aminoguanidine along with morphine. Similarly, co-administration of aminoguanidine inhibited naloxone-induced NO overproduction, but it did not inhibit naloxone-induced elevation of brain glutamate level in morphine-dependent mice. The effect of aminoguanidine on naloxone-induced NO overproduction was potentiated by concurrent administration of dizocilpine or l-NAME and antagonized by concurrent administration of l-arginine. These results provide evidence that blockade of NO overproduction, the consequence of NMDA receptor activation, by aminoguanidine, via inhibition of iNOS, can attenuate the development of morphine tolerance and dependence.     

Effects of agmatine on tolerance to and substance dependence on morphine in mice

目的：观察胍丁胺对吗啡所致耐受和依赖的作用．方法：分别在小鼠耐受和跳跃实验中观察胍丁胺抑制吗啡所致耐受和物质依赖的作用．结果：胍丁胺０１２５－２５ｍｇ·ｋｇ－１剂量依赖性地阻止小鼠对吗啡耐受．用吗啡预处理小鼠使吗啡镇痛ＥＤ５０（２０１,１４４－２８０ｍｇ·ｋｇ－１）与盐水组相比（６３,５１－７８ｍｇ·ｋｇ－１）增加３倍以上．用胍丁胺和吗啡共同预处理小鼠则使吗啡丧失引起耐受的能力．胍丁胺（２５－１０ｍｇ·ｋｇ－１）剂量依赖性地抑制由纳洛酮引起的吗啡依赖小鼠之戒断跳跃和体重减轻．用胍丁胺和吗啡共同处理小鼠使引起小鼠之戒断跳跃所需纳洛酮ＥＤ５０（２１４,１８４－２４ｍｇ·ｋｇ－１）较吗啡处理组（２５,２１－２８ｍｇ·ｋｇ－１）增大８倍．胍丁胺的上述作用均被咪唑克生所阻断．结论：胍丁胺通过激活咪唑啉受体而阻止小鼠对吗啡耐受和依赖．     

利鲁唑对吗啡镇痛、耐受和依赖作用的影响(英文)

目的　研究利鲁唑对阿片镇痛、耐受及躯体功能的调节。方法　采用冰醋酸扭体 ,5 5℃热板法和热辐射甩尾法观察利鲁唑对小鼠痛阈及吗啡镇痛效应的影响 ;采用小鼠急性和慢性吗啡耐受模型及小鼠吗啡依赖模型 ,观察利鲁唑对吗啡耐受和依赖的作用。结果　单独皮下注射利鲁唑 2 .5～ 10mg·kg- 1在以上 3种模型无镇痛作用 ,然而能剂量依赖性地增强吗啡镇痛效应。利鲁唑 2 .5～ 10mg·kg- 1剂量依赖性地对抗吗啡引起的急性和慢性耐受。在小鼠吗啡依赖模型中 ,利鲁唑 2 .5～ 10mg·kg- 1剂量依赖性地抑制吗啡戒断症状的产生。结论　利鲁唑自身无镇痛作用 ,但能显著增强吗啡镇痛效应 ,并能预防吗啡所引起的耐受和依赖     

Effects of nandrolone on acute morphine responses,tolerance and dependence in mice

Anabolic-androgenic steroid exposure has been proposed to present a risk factor for the misuse of other drugs of abuse. We now examined whether the exposure to the anabolic-androgenic steroid, nandrolone, would affect the acute morphine responses, tolerance and dependence in rodents. For this purpose, mice received nandrolone using pre-exposure (for 14 days before morphine experiments) or co-administration (1 h before each morphine injection) procedures. Nandrolone treatments increased the acute hypothermic effects of morphine without modifying its acute antinociceptive and locomotor effects. Nandrolone also attenuated the development of tolerance to morphine antinociception in the hot plate test, but did not affect tolerance to its hypothermic effects, nor the sensitisation to morphine locomotor responses. After nandrolone pre-exposure, we observed an attenuation of morphine-induced place preference and an increase in the somatic manifestations of naloxone-precipitated morphine withdrawal. These results indicate that anabolic-androgenic steroid consumption may induce adaptations in neurobiological systems implicated in the development of morphine dependence.     

Some relations between tolerance and physical dependence to morphine in mice

Tolerance to morphine analgesia and precipatated physical dependence were studied in mice under different conditions. There was a gradual loss of tolerance during the continous absorption of morphine from a pellet. Tolerance was decreased by nalorphine during morphine absorption. An attenuated physical dependence was observed two or four days after a single dose of morphine. In animals previously treated with pellets of morphine, single doses of morphine induced less tolerance than in mice that had never been implanted with pellets; in both cases cycloheximide prevented development of tolerance. Tolerance persisted for more than 20 days after absorption of the morphine pellet. These results reinforce the hypothesis that tolerance and physical dependence are produced by a similar mechanism and that an inhibitory process of tolerance exists.     

胍丁胺对吗啡所致小鼠耐受和物质依赖的作用

目的 观察胍丁胺对吗啡所致耐受和依赖的作用。方法 分别在小鼠耐受和跳跃实验中观察胍丁胺抑制吗啡所致耐受和物质依赖的作用,结果：胍下胺０．１２５～２．５ｍｇ．ｋｇ＾－１剂量依赖性地阻止小鼠对吗啡耐受,用吗啡预处理小鼠使吗啡镇痛ＥＤ５０（２０．１,１４．４－２８．０ｍｇ．ｋｇ＾－１）与盐水组相比（６．３,５．１－７．８ｍｇ．ｋｇ＾－１）增加３倍以上,用胍丁胺和吗啡共同预处理小鼠则使吗啡丧失引直耐受的能     

The effects of D-histiding on the expression of morphine tolerance and physical dependence in mice

D-Histidine, administered in the 'wthdrawal' phase of morphine addiction, failed to modify the expression of tolerance and physical dependence in mice. L-Histidine, on the contrary, can enhance tolerance and inhibit physical dependence. Whole brain histamine is markedly increased by L-histidine administration, but only minimally by D-histidine. This confirms that the actions of L-histidine on morphine addiction are stereospecific, and so can be more confidently correlated with the increase in brain histamine levels produced by the natural amino acid precursor.     

Effect of selective monoamine oxidase inhibitor drugs on morphine tolerance and physical dependence in mice

Clorgyline and Lilly 51641, given at dose levels that inhibited selectively brain type A monoamine oxidase (MAO), significantly lowered the incidence of stereotyped jumping produced by naloxone in mice rendered dependent on morphine by subcutaneous implantation of a pellet of the drug. In contrast, selective inhibition of brain type B MAO by deprenyl or pargyline, or nonspecific inhibition of both type A and type B MAO by high doses of Lilly 51641 or pargyline did not modify the abstinence syndrome. Tolerance to the analgesic effect of morphine was unchanged regardless of the enzyme form blocked. The attenuation of withdrawal jumping by low doses of clorgyline or Lilly 51641 does not seem related to changes in brain dopamine. which was found to be deaminated by both enzyme types. The results suggest the possible implication of different and interrelated neurochemical systems in the development of morphine dependence in mice.     

Possible mechanisms of action in melatonin reversal of morphine tolerance and dependence in mice

In our earlier study, we reported the ability of melatonin to reverse the development of morphine tolerance and dependence in mice. In the present study, we attempted to analyse the possible involvement of putative melatonin receptors, central and peripheral benzodiazepine receptors and the nitric oxide (NO) system in the mechanism of melatonin reversal of morphine tolerance and dependence in mice. Co-administration of L-N(G)-nitro arginine methyl ester (L-NAME) or melatonin with morphine during the induction phase (days 1-9) delayed the development of tolerance to the anti-nociceptive action of morphine and also reversed naloxone precipitated withdrawal jumpings. L-arginine administration during the induction phase enhanced the development of tolerance to the anti-nociceptive effect of morphine but had no effect on the naloxone-precipitated withdrawal response. During the expression phase (day 10), acute administration of melatonin or L-NAME reversed, whereas L-arginine facilitated, naloxone-precipitated withdrawal jumping in morphine-tolerant mice, but none of these drugs affected the nociceptive threshold in morphine-tolerant mice. Further, co-administration of melatonin or L-NAME with L-arginine during the induction phase antagonized later the effects on the development of morphine tolerance. Also, prior administration of melatonin or L-NAME reversed the L-arginine potentiation of naloxone-precipitated withdrawal jumping in morphine tolerant mice. Among the antagonists for putative melatonin receptors studied, neither luzindole (melatonin MT1 and MT2 receptor antagonist) nor prazosin (melatonin MT3 receptor antagonist) antagonized the melatonin reversal of morphine tolerance and dependence. 1-(2-Chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinolinecarboxam ide (PK11195), a peripheral but not central benzodiazepine receptor antagonist, flumazenil, partially antagonized the melatonin reversal of naloxone-precipitated withdrawal jumping in morphine-dependent mice, but had no effect on the reversal of morphine tolerance induced by melatonin. Overall, the present observations suggest that the melatonin-induced reversal of morphine tolerance and dependence may involve its ability to suppress nitric oxide synthase (NOS) activity. Further, the melatonin-induced reversal of morphine tolerance and dependence is not mediated through its actions via putative melatonin receptors. The agonistic activity of melatonin towards peripheral benzodiazepine receptors may partially contribute to the suppression of morphine dependence but not to the reversal of tolerance to the analgesic activity of morphine.     

Repeated administration of nicotine attenuates the development of morphine tolerance and dependence in mice

Clinical use of morphine in pain management is a controversial issue. Both nicotine and morphine are widely abused. So, investigating the interaction between nicotinic and opioid receptors is of great interest to both basic mechanistic and clinical view. We investigated the influence of repeated administration of nicotine on the development of morphine tolerance and dependence. Adult male albino mice were rendered dependent on morphine by subcutaneous (s.c.) injections three times daily for 3 days. Repeated intraperitoneal (i.p.) injection of nicotine (0.001-2 mg/kg) or saline (1 ml/kg) was performed 15 min prior to each morphine injection. Maximal possible effect (MPE%) of morphine (50 mg/kg; s.c.) was used on the fourth day as an index for the development of tolerance. Likewise, to assess the occurrence of dependence in drug-treated mice, naloxone (5 mg/kg; i.p.) was injected 2 h after the last dose of morphine. Repeated nicotine administration significantly attenuated the development of tolerance in a dose-dependent manner whereas it significantly decreased withdrawal jumping behavior in a biphasic profile (V-shape) manner. Furthermore, the central nicotinic receptor antagonist mecamylamine (0.01-0.1 mg/kg; i.p.) neither the peripheral nicotinic receptor antagonist hexamethonium (0.01 and 0.1 mg/kg; i.p.) nor the muscarinic receptor antagonist atropine (2.5-10 mg/kg; i.p.), dose-dependently antagonized both the inhibition of withdrawal jumping as well as increase in MPE% which was produced by repeated nicotine administration (0.1 mg/kg; i.p.). On the other hand, 3 days of solely nicotine treatment resulted in significant jumping behavior precipitated by naloxone after single morphine injection on the test day. The data suggests that the inhibitory effect of nicotine on the morphine tolerance and dependence is mediated by central nicotinic receptors and there is a cross-dependence between nicotine and morphine.     

Antidiuretic effect of morphine in the rat: tolerance and physical dependence.

1 Injection of rats with morphine or methadone, before they received a water load equivalent to 5% of their body weight, produced a dose-dependent antidiuretic effect. Following the antidiuresis, urine was eliminated with kinetics similar to control untreated rats. 2 The antidiuretic effect of morphine or methadone was blocked by naloxone administered before the opiate, or reversed when given after the opiate. 3 Rats implanted with morphine pellets developed a marked degree of tolerance to the antidiuretic effect of morphine. Tolerance was also obtained on injection of three daily doses of morphine or methadone over two days. 4 Withdrawal symptoms were precipitated by naloxone in rats implanted with pellets of morphine; under these conditions the animals showed a marked reduction in urine production as compared to naive rats.     

Cynomolgus monkeys and morphine tolerance and dependence

Cynomolgus monkeys readily developed tolerance to and physical dependence on morphine indistinguishable from that produced by an identical dose regimen in rhesus monkeys.     

The effects of FK506 on the development and expression of morphine tolerance and dependence in mice

FK506 is an immunophilin-binding ligand that inhibits calcineurin and decreases nitric oxide (NO) production in the nervous tissues. We examined the effects in mice of systemic treatment with FK506 on the induction and expression of morphine (s.c.) tolerance and dependence and compared them with the effects of the non-specific NO synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME), and specific inducible NO synthase inhibitor, aminoguanidine. FK506 (0.5-10 mg/kg, s.c.) exerted inhibitory effects on both development and expression of tolerance to morphine-induced antinociception. FK506 also significantly decreased the expression of morphine dependence, as assessed by naloxone-precipitated (2 mg/kg, i.p.) withdrawal syndrome, but a similar effect was not found for the development of morphine dependence. A similar pattern of effects was observed with L-NAME (3-20 mg/kg, i.p.), while aminoguanidine (50-100 mg/kg, i.p.) did not alter tolerance or dependence. Examining the possible interaction between their inhibitory effects on tolerance and dependence, we combined the subeffective doses of FK506 (0.5 or 1 mg/kg) with L-NAME (3 mg/kg) or aminoguanidine (100 mg/kg). The combination of FK506 with L-NAME, but not with aminoguanidine, significantly decreased the development and expression of tolerance and expression of dependence. These data show the effectiveness of FK506 on morphine tolerance and dependence and suggest an additive effect between FK506 and the inhibition of constitutive NO synthesis in this regard.     

Antagonism by naloxone of tolerance and dependence in mice given a single dose of morphine

The effect of naloxone given at various times after morphine administration on the development of tolerance to and dependence on a single dose of morphine was studied. Naloxone antagonized the analgesic effect of morphine and the development of tolerance to and dependence on morphine, dose dependently. The time course of the development of tolerance to a single dose of morphine almost paralleled that of dependence on morphine but the time course of the disappearance of tolerance did not coincide with that of dependence. When start of the duration of action of morphine was blocked by naloxone for various time intervals, the degree of tolerance to and dependence on morphine was antagonized, time dependently. When the end of the duration of action of morphine was antagonized by naloxone for various time intervals, tolerance and dependence which developed up to that time was completely antagonized by naloxone.