6β-纳曲醇与纳曲酮拮抗吗啡镇痛作用的比较

目的　比较 6 β 纳曲醇 ( 6 β naltrexol,6 β NOL)与纳曲酮 (naltrexone ,NTX)拮抗吗啡的镇痛作用。 方法　用小鼠热板法和小鼠热辐射甩尾法 ,sc和ig两种途径研究 6 β NOL和NTX拮抗吗啡镇痛作用的强度和有效时间。用放射配体结合实验研究 6 β NOL和NTX对阿片受体的亲和力。 结果　小鼠热板法和甩尾法显示 ,6 β NOL的抗吗啡镇痛作用强度和有效时间分别约为NTX的 ( 6 1± 1 7) %和 3～ 4倍 ;po拮抗吗啡镇痛作用强度约为sc的 30 % ,与NTX相近。在受体水平 ,6 β NOL对阿片 mu受体的亲和力约为NTX的 12 5 % ,这与它们在整体水平拮抗吗啡镇痛作用的强度相近。结论　 6 β NOL抗吗啡镇痛作用比NTX弱 ,但作用时间长     

纳曲酮与纳洛酮对吗啡，依托尼秦及羟甲芬太尼的拮抗作用比较

在整体和受体水平对阿片受体拮抗剂纳曲酮和纳洛酮对吗啡，依托尼秦和［３Ｈ］羟甲芬太尼的拮抗作用进行了比较．研究表明，在整体水平，纳曲酮在很小剂量下就能对抗吗啡在小鼠的镇痛作用，小鼠吗啡急性中毒以及依托尼秦致大鼠翻正反射消失．与纳洛酮相比，纳曲酮强效，长效，ｉｇ有效．受体水平纳曲酮抑制［３Ｈ］羟甲芬太尼与大鼠脑阿片受体结合的强度是纳洛酮的３．６倍，与整体水平实验结果一致。     

纳曲酮与纳洛酮对吗啡,依托尼秦及羟甲芬太尼的拮抗作用…

在整体和受体水平对阿片受体拮抗剂的纳曲酮和纳洛酮对吗啡，依托尼秦和「＾３Ｈ」羟甲芬太尼的拮抗作用进行了比较。研究表明，在整体水平，纳曲酮在很小剂量下就能对抗吗啡在小鼠的镇痛作用，小鼠吗啡急性中毒以及依托尼秦致大鼠翻正反射消失。     

纳曲酮微球的体外释药和对小鼠吗啡镇痛的影响

目的:探讨四种纳曲酮缓释微球的体外释放及其对体内吗啡镇痛效果的影响。方法:用高效液相色谱法检测四种纳曲酮微球体外释放。用小鼠热板法评价它们对吗啡镇痛作用的拮抗效果。结果:微球中PLGA的组成对纳曲酮微球的体外释药及其拮抗吗啡镇痛的作用有显著影响。给药后第八天,以PLGA50:50为载体的两种微球体外释药已达80％以上,且失去了对吗啡的拮抗作用。以PLGA 75:25为载体,含药量分别为20％和30％的微球分别在给药后40天和30天,其体外释药达95％,这两种微球拮抗吗啡的作用也分别持续了约40天和30天。提高药物含量加快了药物的体外释放,也缩短了微球有效作用的时间。结论:微球中药物的体外释放与其拮抗吗啡镇痛作用的效果有良好的相关性。     

纳曲酮微球缓释制剂的药效学研究

本研究目的为观察纳曲酮微球缓释制剂抗吗啡镇痛和成瘾的药效学,药代动力学,组织相容性及生物降解性,为临床应用提供依据。通过小鼠热板法、大鼠甩尾法和吗啡依赖催促实验表明,纳曲酮微球缓释制剂单次皮下给药后对抗吗啡的镇痛作用和阻断小鼠吗啡躯体依赖形成的有效时间均达一个月以上,药代动力学研究证明,大鼠皮下给药有效血药浓度均能维持30天以上,注射局部的病理检查,无明显局部刺激反应,组织相容良好;在大鼠皮下微球约50天内完全降解。     

精氨酸及精氨酸脱羧酶抗体对痛阈及吗啡镇痛作用的影响(英文)

目的进一步阐明胍丁胺对阿片药理作用的影响。方法采用小鼠醋酸扭体法、小鼠热辐射甩尾法、小鼠热板法评价了精氨酸及精氨酸脱羧酶抗体对痛阈、吗啡镇痛及其耐受作用的影响。结果在小鼠醋酸扭体实验中,脑室注射精氨酸能剂量依赖性地抑制小鼠扭体次数,最大抑制率达84 %。在小鼠热辐射甩尾模型中,精氨酸不影响小鼠的甩尾时间,但能剂量依赖性地增强吗啡的镇痛作用,使吗啡2 .5 mg·kg-1的最大可能镇痛百分率从23 %增加到71 %。此外,在小鼠热辐射甩尾实验中,精氨酸能抑制吗啡100 mg·kg-1所诱导的急性耐受。精氨酸上述作用可被咪唑啉受体拮抗剂咪唑克生(3mg·kg-1,ip)所抑制。在小鼠热辐射甩尾实验和小鼠55℃热板实验中,精氨酸脱羧酶抗体能抑制吗啡镇痛,并能加重吗啡所致的耐受。结论上述结果提示,精氨酸及精氨酸脱羧酶在痛阈、吗啡镇痛及吗啡依赖形成过程中具有重要作用。     

1,6-二(4-苯乙基-1-甲基-1-哌嗪基)己烷二溴化物的镇痛活性研究

目的　研究哌嗪类新化合物 1,6 二 (4 苯乙基 1 甲基 1 哌嗪基 )己烷二溴化物 (97 9 G4 )的镇痛作用及机制。方法　通过醋酸扭体模型、热板、甩尾、纳洛酮拮抗试验及豚鼠回肠离体标本研究样品的镇痛活性及机制。结果　sc 97 9 G4 5mg·kg-1即可有效抑制小鼠扭体反应 (P <0 0 5 ) ,ID50为 8 8mg·kg-1;sc 4 0mg·kg-1、icv 2 5 μg·kg-1均可延长热板实验的舔足阈 (P <0 0 5 ) ;sc 2 0mg·kg-1可延长甩尾试验的潜伏期 (P <0 0 1) ;纳洛酮可拮抗其镇痛活性 ;97 9 G4可激动豚鼠回肠离体标本上的阿片受体。结论　 97 9 G4具有的镇痛活性 ,主要作用部位在中枢 ,其镇痛活性可被纳洛酮拮抗 ,但作用特点有别于吗啡     

野罂粟总生物碱镇痛作用

目的：研究野罂粟总生物碱（total alkaloids of Papaver nudicaul，TAPN）的镇痛作用特点。方法：采用小鼠热板法和大鼠电刺激甩尾法两种致痛模型研究TAPN镇痛作用特点。结果：小鼠热板法和大鼠电刺激甩尾法致病实验结果表明：ipTAPN具有明显的镇痛作用，其作用强度约为吗啡的1／5～1/4。单次给药的镇痛作用达峰时间与吗啡相似，均在20min以内，但镇痛作用持续时间明显长于吗啡，可达4h以上。与吗啡明显不同的是．TAPN的镇痛作用无耐受性。结论：TAPN具有明显的镇痛作用，作用强度弱于吗啡．约为吗啡的1／5-1/4，但镇痛作用维持时间明显长于吗啡，可持续4h以上．且其镇痛作用无耐受性。     

纳屈酮对吗啡和海洛因产生依赖的影响

本文观察了纳屈酮对吗啡和海洛因在大、小鼠产生依赖的影响。纳屈酮2.0-4.0mg·kg~(-1)或1.8-3.6mg·kg~(-1)po分别可对抗吗啡和海洛因在小鼠产生身体依赖;1.0-3.0mg·kg~(-1)sc可拮抗吗啡致小鼠条件性位置偏爱的形成。当吗啡诱发小鼠条件性位置偏爱形成后,纳屈酮可加速其消退。提示纳屈酮对小鼠吗啡精神依赖的产生和消退有一定影响。参考上述实验结果和人与动物间剂量折算,我们认为小剂量纳屈酮10-15mg·d~(-1)po防止阿片依赖病人戒毒后复吸是可行的。     

左旋精氨酸及左旋精氨酸脱羧酶抗血清对吗啡镇痛及耐受的影响

目的:分析左旋精氨酸及左旋精氨酸脱羧酶(L-ADC)对吗啡镇痛及其所致耐受的影响。方法:用家兔制备L-ADC多克隆抗体;以小鼠热辐射甩尾法和小鼠55℃热板测痛模型分析此抗体及左旋精氨酸对吗啡镇痛和耐受的影响。结果:在热辐射甩尾和热板测痛模型中,0.5-50mg·kg~(-1)的左旋精氨酸(sc)不影响吗啡镇痛和耐受(P>0.05)。L-ADC抗血清(脑室注射,1:1000-1:10稀释)能对抗吗啡镇痛作用,在热辐射甩尾和热板测痛模型中,它能使吗啡可能最大镇痛百分率分别从94.3％和80.6％下降到57.7％和42.9％(P<0.01)。吗啡连续处理小鼠3d后形成耐受:在热辐射甩尾和热板测痛模型中,吗啡的可能最大镇痛百分率分别从90.3％和80.3％下降到47.2％和40.5％;L-ADC抗血清能进一步加重吗啡所致耐受,其可能最大镇痛百分率进一步下降至19.8％和27.7％(P<0.01)。结论:L-ADC可能参与调节了吗啡镇痛及耐受形成过程;而左旋精氨酸不影响吗啡镇痛和耐受。     

Kinetics and inhibition of the formation of 6beta-naltrexol from naltrexone in human liver cytosol

AIMS: To determine the kinetics of the formation of 6beta-naltrexol from naltrexone in human liver cytosol, and to investigate the role of potential inhibitors. METHODS: The kinetics of the formation of 6 beta-naltrexol from naltrexone were examined in eight human liver cytosol preparations using h.p.l.c. to quantify 6 beta-naltrexol and, the extent of inhibition of 6 beta-naltrexol formation was determined using chemical inhibitors. The formation of 6 beta-naltrexol and the back reaction of 6 beta-naltrexol to naltrexone were also examined in a microsomal preparation. RESULTS: The Vmax, Km and CLint values for the formation of 6 beta-naltrexol from naltrexone were in the ranges of 16-45 nmol mg-1 protein h-1, 17-53 microM and 0.3-2.2 ml h-1 mg-1 protein, respectively. The steroid hormones testosterone (Ki = 0.3 +/- 0.1 microM) and dihydrotestosterone (Ki = 0.7 +/- 0.4 microM) were the most potent competitive inhibitors of 6 beta-naltrexol formation, with naloxone, menadione and corticosterone also producing > 50% inhibition at a concentration of 100 microM. The opioid agonists morphine, oxycodone, oxymorphone and hydromorphone, and a range of benzodiazepines showed < 20% inhibition at 100 microM. In the microsomal preparation, there was no formation of naltrexone from 6beta-naltrexol nor any formation of 6beta-naltrexol from naltrexone. CONCLUSIONS: The intersubject variability in the kinetic parameters of 6beta-naltrexol formation could play a role in the efficacy of and patient compliance with naltrexone treatment. This variability could be due in part to a genetic polymorphism of the dihydrodiol dehydrogenase DD4, one of the enzymes reported to be responsible for the formation of 6beta-naltrexol from naltrexone. DD4 also has hydroxysteroid dehydrogenase activity which could account for the potent inhibition by the steroid hormones testosterone and dihydrotestosterone. The clinical significance of the latter finding remains to be established.     

Comparison of the opioid receptor antagonist properties of naltrexone and 6 beta-naltrexol in morphine-naïve and morphine-dependent mice

It has been proposed that on chronic morphine treatment the micro-opioid receptor becomes constitutively active, and as a consequence, the opioid withdrawal response arises from a reduction in the level of this constitutively active receptor. In support of this, the putative micro-opioid receptor inverse agonist naltrexone has been shown to precipitate more severe withdrawal behavior in mice than the putative neutral receptor antagonist 6 beta-naltrexol. In the present study naltrexone and 6 beta-naltrexol were compared in NIH Swiss mice to test the hypothesis that their differential ability to precipitate withdrawal is due to differences in their in vivo opioid receptor antagonist potencies caused by differential access to micro-opioid receptors in the central nervous system and not necessarily by intrinsic differences in their opioid receptor activity. In na?ve mice both compounds had similar potencies to antagonize morphine-induced antinociception in the hot plate and warm-water tail-withdrawal assays when measured under equilibrium conditions and afforded similar calculated apparent in vivo micro-opioid receptor affinities. In morphine-dependent mice both compounds precipitated withdrawal jumping but naltrexone was between 10- and 100-fold more potent than 6 beta-naltrexol. A similar potency difference was seen for other withdrawal behaviors. Both naltrexone and 6 beta-naltrexol at 1 mg/kg reversed antinociception induced by the long-lasting micro-opioid receptor agonist BU72 in the warm-water tail-withdrawal assay, but antagonism by naltrexone was 6-fold more rapid in onset at equal doses. Since the compounds have similar affinity for the micro-opioid receptor in vivo, the results suggest that the differences observed between the ability of naltrexone and 6 beta-naltrexol to precipitate withdrawal in the mouse may be explained by differential onset of receptor antagonist action.     

Conjugate addition ligands of opioid antagonists. Methacrylate esters and ethers of 6 alpha- and 6 beta-naltrexol

Alpha- and beta-naltrexol derived esters 9 and 10 and ethers 11 and 12, each containing the alpha, beta-unsaturated ester functionality, were prepared as conformationally more flexible analogues of spiro-alpha-methylene-gamma-lactones 5 and 6. All were active in the opioid radioreceptor binding assay against [3H]bremazocine and more active against [3H]DAGO, indicating mu-subtype selectivity, but only ether 12 showed significant irreversible activity. We conclude that small structural changes, made in very closely related electrophilic opioids, lead to changes in receptor binding. All four compounds were long-acting antagonists to morphine in mice, with ester 10 being approximately equipotent with naltrexone.     

Chronic d-amphetamine inhibits opioid receptor antagonist-induced supersensitivity.

Chronic treatment with an opioid antagonist, such as naltrexone, increases opioid receptor density and opioid agonist potency. Since stimulants such as d-amphetamine can increase opioid potency and opioid abusers may administer stimulants during naltrexone treatment, the effect of chronic d-amphetamine on naltrexone-induced opioid receptor upregulation and supersensitivity was examined in mice. Mice were implanted s.c. with a 15 mg naltrexone or placebo pellet for 8 days. Mice were injected daily with saline or d-amphetamine (7.5 or 5.0 mg/kg per day s.c.) for 7 days beginning 24 h following implantation. Naltrexone and placebo pellets were removed on the 8th day, and 24 h later mice were tested for morphine analgesia (tail-flick) or whole brain was removed and opioid receptor binding studies were conducted. Chronic naltrexone significantly enhanced the analgesic potency of morphine in saline-treated mice. However, naltrexone treatment did not increase morphine potency in mice treated with d-amphetamine. In binding studies, naltrexone increased [3H][D-Ala2,NMePhe4,Gly-ol5]enkephalin (DAGO) Bmax (+60-70%) without altering KD in both saline- and d-amphetamine-treated mice. Results from studies with 2 nM [3H][D-Pen2,D-Pen5]enkephalin (DPDPE) were similar. These studies indicate that daily d-amphetamine can limit naltrexone-induced supersensitivity but not receptor upregulation. Thus, upregulation can be dissociated from functional supersensitivity.     

Evaluation of receptor mechanism mediating fentanyl analgesia and toxicity.

In the present study the antagonism of fentanyl pharmacodynamics was studied in the mouse and the receptor populations mediating the analgesic and lethal effects of fentanyl were examined. Both 1 and 8 days following implantation (s.c.) of a 15 mg naltrexone pellet there was a significant shift to the right of the fentanyl dose-response curves for analgesia and lethality. The analgesia dose-response curves were shifted significantly more (80- to 264-fold) than the lethality curves (13- to 16-fold) in the presence of naltrexone. In addition, acute naloxone (0.1 mg/kg s.c.), antagonized fentanyl analgesia more than lethality. Consequently, the relative safety ratio of fentanyl (LD50/ED50) was decreased in the presence of opioid antagonists. Pretreatment with naloxonazine (35 mg/kg s.c.) 24 h prior to testing effectively inhibited fentanyl-induced analgesia, but not fentanyl-induced lethality. However, pretreatment with beta-funaltrexamine (beta-FNA) (20 mg/kg, s.c.) 24 h prior to testing inhibited both fentanyl-induced analgesia and lethality. Implantation (s.c.) of a 75 mg morphine pellet for 72 h resulted in cross-tolerance to both fentanyl analgesia and lethality. However, the degree of the cross-tolerance was 1.8-fold for analgesia and 4.5-fold for lethality. Displacement studies of [3H]naltrexone by fentanyl in mouse brain homogenate indicated two populations of binding sites. Taken together, the pharmacodynamic studies and the binding studies suggest that fentanyl exerts its analgesic and lethal effects through different receptor populations.     

Chronic opioid antagonist treatment: assessment of receptor upregulation

Changes in specific brain opioid binding and opioid pharmacodynamics were determined in mice treated with the opioid antagonist naltrexone (subcutaneously implanted pellets) for 8 days. Chronic opioid antagonist treatment increased the number of binding sites (upregulation) for [³H]naloxone (+55%) and [³H][D-Ala²,D-Leu⁵]enkephalin (+41%) but did not alter the affinity of the ligands, as determined in saturation studies. Displacement studies of [³H]naloxone by morphine also indicated that there was no change in morphine's affinity. In vivo estimation of naloxone affinity (pA₂), agreed with the in vitro results indicating that chronic naltrexone treatment did not alter naloxone affinity. Chronic naltrexone treatment (0.5, 1.0, 15.0 mg pellets) increased the analgesic potency of morphine (supersensitivity) in a dose-dependent manner, up to a maximal increase in relative potency of 1.8. However, in mice tested with the naltrexone pellets still implanted, the 15 mg naltrexone pellet was able to shift the dose-response function for morphine analgesia more than 300-fold. The lowest dose naltrexone pellet (0.5 mg), produced significant antagonism of morphine analgesia, but did not produce significant supersensitivity. Thus, supersensitivity and upregulation are not proportional to the degree of antagonism of opioid effects; and supersensitivity in the mouse is related to increased binding sites and not to changes in receptor affinity as determined by in vivo and in vitro methods.     

Vivitrex, an injectable, extended-release formulation of naltrexone, provides pharmacokinetic and pharmacodynamic evidence of efficacy for 1 month in rats.

While oral naltrexone is effective in treating alcohol and opiate dependencies, poor patient adherence and widely fluctuating plasma levels limit its efficacy. To overcome these problems, an extended-release formulation of naltrexone (Vivitrex) was developed by encapsulating naltrexone into injectable, biodegradable polymer microspheres. Pharmacokinetic studies in rats demonstrated that this formulation produced stable, pharmacologically relevant plasma levels of naltrexone for approximately 1 month following either subcutaneous or intramuscular injections. While rats receiving placebo microspheres demonstrated a pronounced analgesic response to morphine in the hot-plate test, morphine analgesia was completely blocked in rats treated with extended-release naltrexone. This antagonism began on day 1 following administration and lasted for 28 days. Rats reinjected with extended-release naltrexone 34 days after the initial dose and tested for another 35 days showed consistent suppression of morphine analgesia for an additional 28 days. mu-Opioid receptor density, as measured by [(3)H]DAMGO autoradiography, increased up to two-fold following a single injection of extended-release naltrexone. Saturation binding assays using [(3)H]DAMGO showed changes in the midbrain and striatum at 1 week after extended-release naltrexone administration, and after 1 month in the neocortex. These receptor increases persisted for 2-4 weeks after dissipation of the morphine antagonist actions of naltrexone. These data suggest that therapeutically relevant plasma levels of naltrexone can be maintained using monthly injections of an extended-release microsphere formulation, and that changes in mu-opioid receptor density do not impact its efficacy in suppressing morphine-induced analgesia in the rat. Clinical trials of extended release naltrexone for treating alcohol and opiate dependency are currently ongoing.     

Metabolism and disposition of naltrexone in man after oral and intravenous administration

The metabolism and elimination of [15, 16,-3H2]naltrexone was studied in man after oral and intravenous administration. The same metabolites, although in varying proportions, were observed in both cases; conjugated naltrexone and conjugated and unconjugated 6 beta-naltrexol were the major metabolites observed in plasma, urine, and feces. 2-Hydroxy-3-O-methyl-6 beta-naltrexol was found in minor quantities. Naltrexone was almost completely absorbed after oral administration. After oral and intravenous administration of naltrexone, about 60% of the dose was recovered in the urine in 48 and 72 hr, respectively. The route of administration did not significantly affect urinary clearance values obtained for unconjugated or conjugated naltrexone and 6 beta-naltrexol. The route of administration significantly affected terminal plasma half-life values obtained for unconjugated naltrexone (2.7 hr, iv; 8.9 hr, oral), but had little effect on comparable values obtained for total drug, conjugated naltrexone, and unconjugated and conjugated 6 beta-naltrexol. Combined gas chromatography-mass spectrometry was used to validate the presence of naltrexone, 6 beta-naltrexol, and 2-hydroxy-3-O-methyl-6 beta-naltrexol in urine.     

Pharmacokinetics of morphine and its surrogates V: Naltrexone and naltrexone conjugate pharmacokinetics in the dog as a function of dose

Sensitive reversed-phase HPLC assays with electrochemical detection, developed to quantify naltrexone, 6 beta-naltrexol, and their conjugates in biological fluids, provided assay sensitivities of 2-14 ng/mL in plasma, urine, and bile. Plasma, urine, and bile were monitored in dogs after bolus administrations of 0.5 and 5.0 mg/kg iv naltrexone hydrochloride. Plasma-time data showed two sequential half-lives of 5 +/- 1 (SEM) and 47 +/- 5 min. Pharmacokinetics were dose-independent; total and renal clearances were 1043 +/- 98 mL/min and 72 +/- 11 mL/min, respectively, with a similar renal clearance (85 +/- 12) for the conjugate. The percentages of the dose excreted in the urine as naltrexone and its conjugate were 7 +/- 1% and 58 +/- 3%, respectively, with the remainder being excreted in the bile as conjugates. As much as 36% was collected as conjugate in the total bile of the bile-cannulated dog. There was no biliary secretion of unchanged naltrexone. The conjugate was apparently enterohepatically recirculated. 6 beta-Naltrexol is not a metabolite of naltrexone in dogs. Within the limits of analytical detection (2 ng/mL) neither 6 beta-naltrexol nor its conjugates appeared in any monitored biological fluids when such fluids were assayed quickly after sampling.