Decrease of tolerance development to morphine by 5-hydroxytryptophan and some related drugs

The administration of 5-hydroxytrytophan (5-HTP) produced a hyperalgesic state in mice tolerant to the analgesic action of morphine. This effect was counteracted by p-chlorophenylalanine (p-CPA) which uncovered the analgesic effect of the serotonin precursor, observed in nontolerant animals. 5-HTP administered prior to various doses of morphine decreased tolerance to the opiate. This effect was also observed in animals treated with p-CPA, methysergide or reserpine. The administration of Dopa prior to morphine failed to inhibit development of tolerance to the analgesic. These results provide evidence in favour of the hypothesis that tolerance to morphine is related to a change in serotonin metabolism or reactivity (see Discussion) induced by the analgesic.     

Stress-induced potentiation of morphine-induced analgesia in morphine-tolerant rats

This study was designed to evaluate whether or not rats that were tolerant to the analgesic action of morphine were also tolerant to stress-induced potentiation of morphine-induced analgesia. Rats were trained to drink either solutions of morphine (0.5 mg/ml) or drug-free tap water on a limited access schedule (10 min every 6 hr). The daily intake of morphine averaged 46 mg/kg. Nontolerant and rats tolerant to morphine were tested for morphine-induced analgesia (tail-flick assay), while either unstressed or stressed (i.e. immobilized in Plexiglas cylinders). Morphine produced dose- and time-dependent increases in tail-flick latencies in all groups. Increased sensitivity to analgesia induced by morphine was evident for both nontolerant and tolerant, stressed rats, when compared to their unstressed counterparts. Stress-induced potentiation of morphine-induced analgesia was characterized by dose-related increases in the peak effect and duration of the effect. Stress potentiated the analgesic effect of morphine, comparably in nontolerant (1.7-fold) and tolerant (1.5-fold) rats. Differential tolerance to analgesia induced by morphine and to stress-induced potentiation of morphine-induced analgesia suggests that different mechanisms mediate these two effects.     

Morphine action in grouped and isolated rats and mice

The present study determines the analgesic effects of morphine in grouped and isolated rats and mice. Isolated animals developed altered behavioral patterns, including mouse-killing in rats and mutual aggressiveness in mice. The analgesic effect of morphine was tested by tail compression in rats and by the hot plate for mice. Isolated rats developing mouse-killing behavior had a raised pain threshold, while indifferent animals (nonkillers) responded less to morphine. Isolated mice, particularly low aggressors, gave enhanced responses to morphine.     

Analgesia induced by vaginal stimulation in rats is apparently independent of a morphine-sensitive process

Previous studies have suggested that in rats probing against the vaginal cervix with a glass rod is analgesic, for this stimulus elevates the threshold for eliciting vocalization in response to tail shock. In the present studies pretreatment with naloxone HCl (1 or 10 mg/kg), a potent narcotic antagonist, did not antagonize this vaginal stimulation-induced analgesia. Furthermore, vaginal stimulation was found to exert its analgesic effect even in rats made tolerant to, and dependent upon, morphine sulfate. These results suggest that the analgesic effect of vaginal stimulation is not necessarity mediated by an opiatesensitive neural system. However, we hypothesize that even though vaginal stimulation and other analgesic manipulations may act via different neural substrates, they may nevertheless converge onto a final common mechanism for pain suppression.     

Attenuation of morphine analgesia in rats with lesions of the locus coeruleus and dorsal raphe nucleus.

The nociceptive reflex activity and analgesic effect of morphine were studied in rats using the hind paw stimulation test. The stimulation threshold was significantly increased in animals with bilateral destruction of the locus coeruleus (LC), and was reduced after lesion of the dorsal raphe nucleus (DR). LC lesions produced a selective lowering of noradrenaline (NA) content in the forebrain, while DR lesions resulted in a reduction in serotonin levels. Lesioning both LC and DR significantly reduced both NA and serotonin contents even when the stimulation threshold was not altered. Morphine produced a significant and dose-dependent elevation of the stimulation threshold in sham-operated animals, while morphine analgesia was almost completely inhibited by destruction of LC, DR and both the nuclei. These results imply that a depression of LC-mediated noradrenergic tone results in a decreased sensitivity to painful stimuli, whereas a reduction of raphe-derived serotonergic tone produces the opposite effect against LC. It is suggested, however, that both of these monoamines from the LC and DR are necessary for the analgesic effect of morphine.     

Acute tryptophan depletion blocks morphine analgesia in the cold-pressor test in humans

The effects of depletion of the serotonin precursor,l-tryptophan, on the threshold and tolerance to cold pressor pain, and the analgesic effect of morphine (10 mg intramuscularly), were tested in a double blind trial on human volunteers. Effects on mood were also assessed using the Profile of Mood States and the Addiction Research Center Inventory (ARCI) Scales. To deplete tryptophan, subjects were fed a tryptophan-deficient amino acid mixture 4.5 h before morphine was administered. Controls received the mixture with tryptophan, which is equivalent to a nutritionally balanced protein. The tryptophan-deficient meal reduced plasma tryptophan more than 70% but had no effect on threshold or tolerance to cold pressor pain. After morphine, tolerance to cold pressor pain increased in controls. Tryptophan depletion abolished this analgesic effect. Pain threshold was not altered by morphine. In subjects with normal tryptophan, the analgesic effect of morphine was predicted by the level of plasma morphine-6-glucuronide, but not by the level of morphine. Morphine increased scores on the LSD scale of the ARCI, but had no effect on other measures of mood. Tryptophan depletion also failed to alter mood in these subjects, who had unusually low depression scores before tryptophan depletion.     

Effects of intraventriculary injected 6-OH dopamine or midbrain raphe lesion on morphine analgesia in rats

Two different techniques were employed to measure morphine analgesia, the hot-plate and the tail compression.An intraventricular injection of 6-hydroxydopamine, which produced a marked decrease of brain noradrenaline and dopamine, strongly potentiated the analgesic effect of morphine.The lesion of midbrain raphe, which lowers forebrain serotonin, antagonized morphine analgesia.5-Hydroxytryptophan restored serotonin levels and the analgesic effect of morphine in midbrain raphe lesioned rats.The role of brain serotonin and catecholamines on morphine analgesia is discussed.     

Effect of the Combination of CI-988 and Morphine on Neuropathic Pain after Spinal Cord Injury in Rats

Cholecystokinin is known to be involved in the modulation of nociception and to reduce the efficacy of morphine analgesia. This study investigated the effects of intrathecal administration of morphine and the cholecystokinin type B antagonist CI-988 on below-level neuropathic pain after spinal cord injury in rats. We also examined the interaction of morphine and CI-988 in the antinociceptive effect. Both morphine and CI-988 given individually increased the paw withdrawal threshold to mechanical stimulation in a dose-dependent manner. The combination of ineffective doses of intrathecally administered CI-988 and morphine produced significant analgesic effects and the combination of effective doses resulted in analgesic effects that were greater than the sum of the individual effects of each drug. Thus, morphine showed a synergistic interaction with CI-988 for analgesia of central neuropathic pain.     

Effects of medial raphe and raphe magnus lesions on the analgesic activity of morphine and methadone

The effects of lesions of the raphe nuclei on opiate-induced antinociception and brain serotonin (5-HT) levels were investigated. Lesions of the medial raphe nucleus effectively antagonized the analgesic effects of morphine, but not methadone, and lowered brain 5-HT. The decrement in analgesic activity of morphine was reversed by pretreatment with 5-hydroxytryptophan. Lesions of the raphe magnus, a descending 5-HT system, antagonized the analgesic potency of both morphine and methadone. These experiments indicate a differential effect of 5-HT manipulation on opiate-induced analgesia, suggesting a different mechanism of analgesic action for morphine and methadone.     

大鼠脑室或脊髓蛛网膜下腔注射八肽胆囊收缩素抗血清翻转吗啡耐受

连续6天给大鼠皮下注射递增剂量的盐酸吗啡(5～30mg/kg),则吗啡镇痛效果逐渐减弱,产生耐受。给吗啡耐受的大鼠侧脑室(icv)注射八肽胆囊收缩素(CCK-8)抗血清2μl,可使吗啡耐受作用被翻转50％(P<0.001)。给吗啡耐受的动物以电针刺激,表明电针与吗啡镇痛两者之间有交叉耐受。icv注射CCK-8抗血清可使电针交叉耐受翻转50％以上(P<0.001)。脊髓蛛网膜下腔(ith)注射CCK-8抗血清也可产生类似的作用,但不如icv注射的明显。单独icv或ith注射CCK-8抗血清对痛阈无显著影响。以上结果表明中枢神经系统CNS)中CCK-8可能参与吗啡耐受的形成机理。     

利血平与优降宁对动物痛阈和吗啡镇痛作用影响因素探讨

采用三种测痛方法,观察了利血平、优降宁对小鼠、大鼠正常痛阈和吗啡镇痛作用的影响,结果表明:ip利血平2 mg/kg,优降宁100 mg/kg均能明显抑制小鼠扭体反应;ip利血平1 mg/kg能明显提高小鼠热板反应时间,但ip优降宁75 mg/kg无明显影响;ip利血平6 mg/kg,优降宁75 mg/kg对大鼠甩尾反应时间均无明显影响;利血平(小鼠0.5～1.0 mg/kg,大鼠2 mg/kg ip)能明显对抗吗啡镇痛作用;优降宁(小鼠35 mg/kg,大鼠50 mg/kg ip)能明显增强吗啡镇痛作用,并能“逆转”利血平对抗吗啡镇痛作用。其“逆转”作用的强弱取决于利血平、优降宁给药的先后次序。     

利血平与优降宁对动物痛阈和吗啡镇痛作用影响因素探讨

采用三种测痛方法,观察了利血平、优降宁对小鼠、大鼠正常痛阈和吗啡镇痛作用的影响,结果表明:ip利血平2 mg/kg,优降宁100 mg/kg均能明显抑制小鼠扭体反应;ip利血平1 mg/kg能明显提高小鼠热板反应时间,但ip优降宁75 mg/kg无明显影响;ip利血平6 mg/kg,优降宁75 mg/kg对大鼠甩尾反应时间均无明显影响;利血平(小鼠0.5～1.0 mg/kg,大鼠2 mg/kg ip)能明显对抗吗啡镇痛作用;优降宁(小鼠35 mg/kg,大鼠50 mg/kg ip)能明显增强吗啡镇痛作用,并能“逆转”利血平对抗吗啡镇痛作用。其“逆转”作用的强弱取决于利血平、优降宁给药的先后次序。     

The synergistic effect of concurrent spinal and supraspinal opiate agonisms is reduced by both nociceptive and morphine pretreatment

The antinociceptive effect of morphine administered into the periaqueductal gray (PAG), the intrathecal space (ITH) and concurrently, into both sites (in a 1:1 dose ratio), was assessed in 1) nontolerant rats, 2) rats made tolerant to the effect of morphine on the tail-flick (TF) test and 3) rats that were tested on the TF during chronic saline administration. In nontolerant rats, concurrent morphine injections produced a multiplicative antinociceptive effect (ED50 = 0.392 microgram, total dose) relative to that obtained after separate PAG (ED50 = 2.8 micrograms) or ITH (ED50 = 6.7 micrograms) injections. The multiplicative effect of concurrent morphine administration was significantly reduced in rats made tolerant to morphine (one 3 mg/kg SC injection and TF test per day for six days). Opiate synergy was also reduced but to a smaller extent in rats that were repeatedly tested on the TF during chronic saline administration (one SC injection and TF test per day for six days). Neither chronic morphine nor saline pretreatment altered the dose-response function to intrathecal morphine. However, both morphine and saline pretreatment significantly reduced the antinociceptive effect of morphine administered into the PAG. The data indicate that concurrent morphine administration into the PAG and ITH space results in a synergistic antinociceptive action which is reduced by performance of the nociceptive response, even in the absence of opiate administration. We suggest that the decrease in opiate synergism produced by nociceptive assessment (behavioral tolerance) is mediated supraspinally, while the additional decline resulting from morphine administered in conjunction with the nociceptive tests (opiate tolerance) is mediated by a combined action at spinal and supraspinal sites.     

Study on the receptor subtypes mediating the analgesic action of an enkephalin analog, Tyr-D-Met(O)-Gly-EtPhe-NHNHCOCH3.AcOH (EK-399)

The analgesic action of the enkephalin analog EK-399 (Tyr-D-Met(O)-Gly-EtPhe-NHNHCOCH3.AcOH) and the subtypes of the opiate receptors mediating the action were studied. The analgesic effect of subcutaneously injected EK-399 was ten times as potent as that of morphine in the rat tail flick test. EK-399 had a longer latency time and duration time than morphine. The analgesic action of EK-399 injected into the rat spinal subarachnoid space was about 800 (1800 in molar ratio) times as potent as that of morphine in the hot plate test. EK-399 had high affinities for both mu and delta opiate receptors in the rat brain receptor binding assay. The apparent pA2 values with naloxone were 7.65 for morphine and 5.98 for EK-399 in the rat tail flick test; the difference was significant. A cross tolerance between EK-399 and morphine was examined in the rat tail flick test. Although morphine tolerant rats showed no tolerance to EK-399, EK-399 tolerant rats showed a clear tolerance to morphine. These results indicate that EK-399 has a potent and long lasting analgesic effect via opiate receptors in rats. In addition to mu-receptors, delta-receptors may be involved in its analgesic mechanism.     

Effect of midbrain raphe lesion on the antinociceptive action of morphine and other analgesics in rats

The antinociceptive action of several analgesics was studied by two methods: the hot-plate and the tail compression tests.Lesions of the midbrain raphe, which produce a marked depletion of serotonin in the forebrain, antagonize the analgesic effect of morphine but not that of methadone, meperidine, codeine and propoxyphene.It is concluded that the serotonin involvement suggested for the analgesic action of morphine cannot be generalized to other analgesics.     

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.     

On the role of a central adrenergic mechanism in morphine analgesic action

The influence of drugs interfering with brain monoamine metabolism on morphine analgesia of rats was estimated by the tail pressure method. Central adrenergic stimulation produced by apomorphine, cocaine, pyrogallol or amphetamine led to stereotyped behaviour and elevation of the pain threshold. Lower doses of these drugs potentiated morphine analgesic action. Reserpine, iproniazid and disulfiram weakened morphine analgesic action. α-Methyldopa increased morphine action and (±)-tryptophan did not influence it significantly.     

Studies on the possible role of pharmacokinetics in the development of tolerance to morphine in the rat.

1. The possible role of pharmacokinetics of morphine in the development of tolerance to the analgesic and hyperthermic effects of morphine was studied in the rat. 2. Male Sprague-Dawley rats were made tolerant to morphine by implanting 6 morphine pellets each containing 75 mg of morphine base for 7 days. The assessment of the degree of tolerance to morphine and pharmacokinetic parameters were done 72 hr after pellet removal. 3. Tolerance developed to both the analgesic and hyperthermic effects of morphine as evidenced by decreased responses to morphine in morphine pellet implanted rats compared with placebo pellet implanted rats. 4. The pharmacokinetic parameters, AUC0-->infinity, Cmax, t1/2, k, MRT, Vss and Clt were determined after injecting 5 and 10 mg/kg doses of morphine intravenously to placebo and morphine pellet implanted rats and using a highly sensitive and specific RIA method to quantitate serum levels of morphine. For a 5 mg/kg dose of morphine, the AUC0-->infinity and t1/2 in morphine pellet implanted rats were significantly higher than in placebo pellet implanted rats, but the k value was lower. The other pharmacokinetic parameters for morphine in the two treatment groups did not differ. For 10 mg/kg dose, the only change was an increase in the MRT in morphine tolerant rats when compared to nontolerant rats. 5. The results establish that the development of tolerance to the analgesic and hyperthermic effects of morphine is not related to pharmacokinetics of morphine in serum but may be related to modification of receptor systems in the central nervous system.     

薯渣膳食纤维对吗啡所致便秘的治疗作用

目的:研究薯渣膳食纤维(FFSPD)对吗啡所致便秘的治疗作用及对吗啡镇痛作用的影响.方法:薯渣膳食纤维连续灌胃14 d,观察小鼠摄食量及体重变化;给予吗啡造成小鼠便秘模型,以墨汁胶液在小鼠小肠内推进的距离占小肠全长百分数为指标,观察不同剂量的FFSPD对胃肠推进运动的影响;采用热板法检测小鼠疼痛耐受时间,判断不同剂量的FFSPD对吗啡镇痛作用的影响.结果:各剂量FFSPD均可增加小鼠摄食量和体重(P＜0.05);对吗啡所致便秘具有明显的治疗作用,且对吗啡镇痛作用无明显改变.结论:FFSPD能明显促进肠蠕动,治疗吗啡所致便秘,但不改变吗啡的镇痛作用.临床可与吗啡合用,参与各种疼痛的治疗,而缓解吗啡导致的便秘.     

MPEP对吗啡耐受大鼠脊髓Ⅰ型IP3受体表达的影响

目的:探讨代谢型谷氨酸受体5(mGluR5)拮抗剂MPEP对吗啡耐受大鼠脊髓背角Ⅰ型IP3受体(IP3R-Ⅰ)表达的影响。方法:24只♂SD大鼠,随机分为4组:生理盐水对照组(NS)、吗啡耐受组、吗啡加MPEP组和MPEP组。通过测定大鼠甩尾潜伏期(TFL)评定各组大鼠的热痛阈变化。最后一次给药后次日取大鼠L4-5脊髓,Westernblot测定并比较各组脊髓背角IP3R-Ⅰ蛋白表达量。结果:吗啡组TFL呈下降趋势,但d7后与NS组比较无统计学意义(P>0.05)。吗啡加MPEP组TFL在用药后3-7 d与吗啡组比较差异有显著性(P<0.05)。吗啡组脊髓背角IP3R-Ⅰ表达较NS组升高(P<0.05),吗啡加MPEP组IP3R-Ⅰ的表达低于吗啡组(P<0.05),MPEP组IP3R-Ⅰ表达与NS组无统计学差异(P>0.05)。结论:鞘内重复注射吗啡后IP3R-Ⅰ表达上调。MPEP抑制吗啡耐受发展,机制可能与其抑制IP3R-Ⅰ表达有关。