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.     

Ketoprofen: i.c.v. injection and electrophysiological aspects of antinociceptive effect

The direct action of ketoprofen on the CNS was investigated by electrophysiological techniques in rats made arthritic. Between the 10th and 16th days after the administration of the complete Freund's adjuvant the rats were anesthetized and the drug was injected directly into the cerebral ventricles. The changes in spontaneous and evoked firing of thalamic neurons were investigated. Ketroprofen very rapidly inhibited the nociceptive activity induced by ankle mobilization. The inhibitory effects were maximal at the doses of 20 and 40 micrograms within 5 min and spontaneous activity was also reduced. The time courses of the action of the increasing doses were also measured. In view of the site of injection, the doses and the very rapid start of the effects, the inhibition of spontaneous and evoked neuronal firing supports the view of a direct effect of this drug on the electrical behaviour of the neurons.     

Implementation of an i.v. morphine infusion program in a community hospital.

Pharmacy departments play a role in helping to design and implement a pain management program in community hospitals. The history, documentation of need, and benefits of the program are presented. Protocol guidelines for the intravenous infusion of morphine are outlined, and specific job functions of the nurse and pharmacist members of the pain management team are defined. In addition, the results of a pain management study are reported, which describe the efficacy of the treatment protocol in 22 patients.     

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.     

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.     

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.     

High-technology i.v. infusion devices

Some of the newer high-technology infusion devices commercially available or under development are described. The range of infusion devices includes both controllers and pumps; pumps can be classified by mechanism of operation (peristaltic, syringe, cassette, elastomeric reservoir), frequency or type of drug delivery (continuous or intermittent infusion, bolus dosing, single- or multiple-solution delivery), or therapeutic application (such as the patient-controlled analgesia, or PCA, pump). Advances in infusion technology and computer technology have led to the development of devices with extremely sophisticated drug-delivery capabilities (multiple-rate or multiple-solution programming, operation as pump or controller, or both, and interchangeable applications and settings). Current research in infusion-device technology is focusing on implantable pumps, pumps with chronobiological applications, osmotic-pressure devices, and open- and closed-loop systems. Pharmacists need to keep abreast of the rapidly changing intravenous device marketplace to provide clinical expertise and leadership in the review and evaluation of high-technology drug delivery systems.     

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.     

Different targets for i.v. vs. i.c.v. administered morphine for its effect on colonic motility in dogs

The effects of intracerebroventricular (i.c.v.) or intravenous (i.v.) administration of morphine on colonic motility were investigated in conscious dogs chronically fitted with a strain gauge transducer sutured to the serosa of the proximal colon. Morphine administered i.v. (100 micrograms/kg) or i.c.v. (10 micrograms/kg) induced similar increases in the motility index for about 3 h. The pattern of colonic contractions after i.v. morphine mainly consisted of an increase in the number of phases of contractile activity each lasting about 5 min. Morphine i.c.v. administered induced a peculiar pattern consisting of short (0.5-1.5 min) phases of contractile waves occurring at a high rate (10-15 per h). The effects of i.v. morphine were abolished after previous i.v. (1 microgram/kg) or i.c.v. (0.1 micrograms/kg) administration of naloxone or methyl-levallorphan, a narcotic antagonist with a high peripheral selectivity (100 micrograms/kg i.v., 10 micrograms/kg i.c.v.). The effects of i.c.v. morphine were not modified by previous i.v. or i.c.v. administration of naloxone (100 micrograms/kg). These results suggest that the stimulatory effect of i.v. morphine on colonic motility involves both central and peripheral components. The i.c.v. administration of morphine does not reproduce its central effect when given i.v. but acts on different central receptors.     

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.     

Influence of 5,6-dihydroxytryptamine on morphine tolerance and physical dependence

The intracerebral administration of 5,6-dihydroxytryptamine (5,6-DHT) in the mouse inhibited the development of tolerance to and physical dependence on morphine induced by morphine pellet implantation. Reduction in tolerance development by 5,6-DHT was evidenced by the decreased amount of morphine necessary to produce analgesia and reduction in dependence development by the increase in the amount of naloxone necessary to induce precipitated withdrawal jumping in comparison with morphine-implanted animals receiving saline. Further evidence that 5,6-DHT reduced dependence development on morphine was evidenced by the fact that 5,6-DHT decreased the loss in body weight which occurred after abrupt morphine withdrawal. At the dose of 5,6-DHT used in this study (60 μg of the creatinine sulfate dihydrate 24 hr prior to morphine pellet implantation), the 5-HT level in the brain 4 days later was 75% of that of the control group while catecholamine levels remain unchanged. These studies substantiate the suggestion from this laboratory that central serotonergic system may be associated in the development of morphine tolerance and dependence.     

奥丹西隆对小鼠吗啡身体依赖性的影响

目的　观察 5 HT3受体特异性拮抗剂奥丹西隆 (on dansetron ,Ond)对吗啡身体依赖性的影响。方法　采用小鼠吗啡依赖模型及离体豚鼠回肠吗啡依赖模型。结果　奥丹西隆 12d预防性给药可有效抑制小鼠吗啡戒断反应 ,使其体重降低减小 (Ond 2～ 10 0 μg·kg-1·d-1组 ) ,或体重降低 ,跳跃反应均明显减弱 (Ond 10 0 μg·kg-1·d-1组 )。另外 ,奥丹西隆 (1～ 2 0 μmol·L-1)亦可抑制纳洛酮促发的离体豚鼠回肠收缩。作用均呈剂量依赖性。结论　奥丹西隆预防性的慢性给药可在一定程度上抑制吗啡身体依赖的形成     

Development of morphine tolerance and physical dependence in rats depleted of brain catecholamines by 6-hydroxydopamine

The present study was undertaken to evaluate the roles of brain norepinephrine (NE) and/or dopamine (DA) in the development of morphine tolerance and physical dependence in rats. Rats were permanently depleted of brain catecholamines (CA, i.e. NE + DA) or DA by 6-hydroxydopamine (6-OHDA) treatment alone or desmethylimipramine plus 6-OHDA treatment at two weeks of age. Five weeks after either treatment, twice daily morphine injections were begun and continued for 32 consecutive days. The antinociceptive activity of morphine in the tail-flick test and the naloxone-precipitated abstinence syndrome were periodically observed throughout the course of chronic morphine treatment. A decreased antinociceptive response to morphine occurred in DA-depleted rats in both the non-tolerant and tolerant states, but the development of tolerance was not affected. The antinociceptive effect of morphine was not modified in either non-tolerant or tolerant CA (NE + DA)-depleted rats, nor was the development of tolerance affected. The spontaneous withdrawal syndrome after abrupt cessation of morphine after 32 days of treatment was markedly enhanced in CA-depleted rats. The results suggest that DA may be involved in mediating the antinociceptive effect of morphine, but not in the development of tolerance to that effect.     

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.     

Protective effect of bupropion on morphine tolerance and dependence in mice

Possible reversal of morphine-induced tolerance and dependence by bupropion was studied in mice. A 10-day repeated injection regimen was followed to induce morphine tolerance and dependence. Bupropion (2 and 5 mg/kg) per se, when chronically administered for 9 days, failed to produce any significant change in tail-flick latency compared with the control mice. Chronic administration of bupropion (2 or 5 mg/kg) during the induction phase (days 1-9) delayed the development of tolerance to the antinociceptive action of morphine and also reversed naloxone- (2 mg/kg) precipitated withdrawal jumps. On the other hand, acute administration of bupropion (2 or 5 mg/kg) on day 10, i.e., during the expression phase of morphine dependence, reduced the incidence of naloxone-precipitated withdrawal jumps without affecting tolerance to the analgesic effect. In conclusion, results of the present study suggest the potential use of bupropion in tolerance and dependence.     

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     

咪唑克生对吗啡镇痛、耐受和身体依赖的影响

目的:观察咪唑克生对吗啡镇痛及吗啡所致耐受和躯体依赖的影响.方法:采用小鼠醋酸扭体实验和55℃热板实验观察咪唑克生对基础痛阈及吗啡镇痛作用的影响;采用小鼠热辐射甩尾实验和小鼠55℃热板实验观察咪唑克生对吗啡耐受形成过程的影响;采用大鼠、小鼠身体依赖模型观察咪唑克生对吗啡所致身体依赖的影响.结果:咪唑克生(3-9mg/kg)能显著降低小鼠基础痛阈,抑制吗啡镇痛;加重吗啡所致耐受;诱发大、小鼠发生戒断综合征.结论:咪唑啉受体参与痛阈形成;咪唑克生能抑制吗啡镇痛,加重吗啡所致耐受;并诱发吗啡依赖性动物发生戒断综合征.     

脊髓星型胶质细胞的JNK介导吗啡耐受

目的观察脊髓JNK在大鼠吗啡镇痛耐受过程中的作用。方法对SD大鼠连续7d鞘内注射吗啡(15μg)建立吗啡耐受的动物模型。采用50℃热水甩尾法观察吗啡的镇痛效果;应用免疫组织化学方法检测吗啡耐受过程中脊髓背角磷酸化JNK(pJNK)的表达情况。结果在慢性鞘内注射吗啡的过程中,大鼠脊髓背角pJNK的表达随着吗啡耐受程度的增加而逐步增加,且pJNK主要存在于脊髓星型胶质细胞。吗啡注射前15min鞘内给予JNK特异性抑制剂SP600125(25μg),不仅可以明显抑制吗啡镇痛耐受还可以部分抑制已形成的吗啡耐受。结论脊髓星型胶质细胞JNK的激活可能是吗啡耐受形成和维持的重要机制之一。