Dose-dependent effects of prolyl-leucyl-glycinamide on morphine-induced analgesia, tolerance and dependence

Prolyl-leucyl-glycinamide (PLG) at a low dose (10 ng/mouse) administered intracerebroventricularly (i.c.v.) did not affect morphine analgesia, but produced a greater increase in the ED50 of morphine-pretreated (100 mg/kg of morphine sulfate) mice as compared to control mice. PLG at doses of 10 and 100 micrograms/mouse antagonized morphine analgesia. Development of morphine tolerance was unaffected by 10 micrograms/mouse but antagonized by 100 micrograms/mouse of PLG. Development of morphine dependence was assessed by changes in body weight and temperature during naloxone-induced withdrawal. PLG (10 ng/mouse) potentiated, 10 micrograms/mouse had no effect and 100 micrograms/mouse antagonized development of morphine dependence. PLG at doses of 10 and 100 micrograms/mouse precipitated withdrawal in morphine-dependent mice. When mice were pretreated with 1.0 mg/kg naloxone i.p. 15 min before PLG, all doses of PLG had no effect on morphine analgesia, but potentiated the development of morphine tolerance and dependence. None of the doses of PLG altered whole brain levels of morphine. PLG did not alter the affinity of opioid receptors for etorphine or the maximal number of binding sites but PLG did exhibit a very weak affinity for opioid receptors. These results indicate that PLG potentiated development of morphine tolerance and dependence through a mechanism not involving opioid receptors. However, at very high doses it was a weak opioid receptor antagonist.     

Modification of morphine analgesia and tolerance by flumazenil in male and female rats

This study assessed the effect of the central benzodiazepine receptor antagonist, 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid ethyl ester (flumazenil), on morphine-induced analgesia, locomotor effects, and development of tolerance in rats. The thermally evoked pain (tail flick) response was determined after acute and chronic intraperitoneal (i.p.) administration of morphine and flumazenil, alone and in combination. In acute studies, flumazenil induced weak analgesia unrelated to dose and sex, whereas morphine-induced analgesia was dependent on both dose and sex (male>female). Flumazenil dose-dependently enhanced the analgesic effect of morphine in female but not in male rats. Isobolographic analysis suggested synergism between flumazenil and morphine in female rats, but antagonism in male rats. Flumazenil-induced locomotor changes (alone and with morphine) were related to sex but not dose. Chronic coadministration of flumazenil with morphine enhanced analgesia and attenuated tolerance development in female rats. The findings suggest a possible role for flumazenil as an adjunct with opioids in acute and chronic pain therapy.     

Blockade of morphine-induced place preference by diazepam in mice

The effects of diazepam on morphine-induced place preference were examined in mice. Pretreatment with diazepam (2 mg/kg i.p.) 30 min prior to morphine injection significantly abolished the morphine (5 mg/kg s.c.)-induced place preference, and this effect of diazepam was antagonized by pretreatment with flumazenil. In addition, pretreatment with diazepam prevented the morphine (5 mg/kg s.c.)-induced increase in dopamine turnover in the limbic forebrain. These results suggest that pretreatment with diazepam may suppress the rewarding effects of morphine.     

Y-IP5对小鼠吗啡镇痛、耐受及躯体依赖的影响

目的:评价化合物Y-IP5对小鼠吗啡镇痛、耐受及躯体依赖的影响。方法:采用55℃热板测痛模型分析Y-IP5对小鼠吗啡镇痛和耐受的影响;采用剂量递增法皮下注射吗啡5 d,建立小鼠吗啡依赖模型,评价Y-IP5对小鼠吗啡躯体依赖的影响。结果:在热板测痛模型中,Y-IP5(2.5,5,10 mg.kg-1)不能明显增强小鼠吗啡镇痛作用(P>0.05),Y-IP5(1.25,2.5,5 mg.kg-1)能明显抑制小鼠吗啡镇痛耐受的形成(P<0.05)。伴随吗啡给予Y-IP5(1.25,2.5,5 mg.kg-1)能剂量依赖性地抑制小鼠躯体依赖的形成(P<0.05);在纳洛酮催促前单次给予Y-IP5(1.25,2.5,5 mg.kg-1),不能显著抑制小鼠吗啡躯体依赖的表达(P>0.05)。结论:Y-IP5对吗啡耐受及躯体依赖的形成可能有一定的干预作用。     

Potentiation of the morphine-induced respiratory rate depression by captopril

The effects of morphine and captopril, an angiotensin-converting enzyme inhibitor, on respiratory frequency have been investigated in non-anesthetized mice. Morphine (10.0 mg/kg) reduced the respiratory frequency which gradually returned to the control level 2 h after the injection. The same dose of morphine when given together with captopril (0.1 and 1.0 mg/kg), caused a similar reduction in respiratory rate. This respiratory depression however, persisted until the end of the observation period. Similar results were obtained with the same dose of morphine in mice pretreated with captopril. The minimal dose of morphine reducing respiratory frequency (3.0 mg/kg), when given to the mice pretreated with captopril (0.1 mg/kg) caused a significant reduction in respiratory frequency and this effect was equal to that obtained with 10.0 mg/kg morphine alone. The results are discussed from the point of the possible inhibitory effect of captopril on the enkephalin degrading enzyme(s).     

Conditioning of morphine-induced taste aversion and analgesia

The process of selective associations is evident in the aversive conditioning literature, where it has been shown that external cues are readily associated with peripheral pain, whereas taste cues are more easily associated with effects of drug administration. Within this framework, it is of interest that the failures to obtain a conditioned analgesic response to a morphine-associated CS have used external cues as conditioned stimuli. In Experiment 1, subjects re-exposed to a morphine-associated CS not only expressed the anticipated taste aversion, but also exhibited a decrease in pain sensitivity that was evident 15 or 30 min following CS re-exposure. Experiment 2 suggested that the conditioned analgesic response was opioid mediated, as pre-test administration of naloxone blocked expression of the analgesic CR. In Experiment 3, an increase in opiate receptor sensitivity produced by chronic naltrexone treatment did not affect the strength of the taste aversion, but resulted in an increase in the magnitude of the conditioned analgesic response. Collectively, these data suggest a neuropharmacological dissociation in systems mediating the two responses.     

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.     

The effect of chronic administration of caffeine on morphine-induced analgesia, tolerance and dependence in mice

Morphine-induced analgesia, and the development of morphine-induced tolerance and dependence was determined in mice which had drunk caffeinated water (1 mg/ml) for 14 days or in mice which had received (-)-N6-(phenylisopropyl)-adenosine (PIA) 1 mg/kg i.p. for 14 days. Analgesia was assessed by the tail flick assay. The development of dependence was assessed by determining the ED50 of naloxone to precipitate withdrawal jumping (3 h after 100 mg/kg morphine pretreatment or 72 h after s.c. implantation of a morphine 75 mg pellet) and by determining the extent of naloxone-precipitated hypothermia in morphine-implanted animals. In mice chronically administered caffeine, the ED50 for morphine-induced analgesia was significantly decreased while the naloxone ED50 for withdrawal jumping increased by 2-fold after both types of morphine pretreatment. In control animals (tap water for 14 days), doses of 1 and 10 mg/kg of naloxone caused significant hypothermia in morphine-implanted animals. Doses of naloxone up to 100 mg/kg did not cause significant hypothermia in morphine-implanted animals which had received chronic caffeine. The development of tolerance was determined by computing the morphine potency ratio for the tail flick assay (tolerant ED50/control ED50). In mice chronically administered caffeine, the potency ratio was decreased significantly in morphine-implanted animals when compared to control. Morphine-induced analgesia, tolerance and dependence was not changed significantly in animals chronically administered PIA. Neither the distribution of morphine to the brain nor the opioid receptor binding parameters for [3H]etorphine and [3H]naltrexone were altered in mice chronically administered caffeine or PIA.(ABSTRACT TRUNCATED AT 250 WORDS)     

Interaction between ACTH fragments, brain opiate receptors and morphine-induced analgesia.

The present study confirms that N-terminal fragments of ACTH have an affinity for rat brain opiate receptors in vitro. Such peptides, devoid of corticotrophic activity, were found to inhibit morphine-induced analgesia if they also possessed affinity for opiate receptors in vitro. The structure-activity relationship for these two parameters is comparable to that observed for the same peptides on the induction of excessive grooming.     

Facilitation of morphine-induced tolerance and physical dependence by prolyl-leucyl-glycinamide

The pretreatment of mice with 30 mg/kg morphine s.c. did not alter the analgesic effect of morphine in mice pretreated with saline but decreased the analgesic effect of morphine in mice pretreated with prolyl-leucyl-glycinamide (PLG). Tolerance was evaluated by the effect of PLG on morphine-induced enhancement of naloxone potency which is a measure of the capacity of naloxone to antagonize morphine-induced analgesia and is postulated to be an indicator of tolerance development. The naloxone potency of PLG-treated mice was 2-fold greater than that of control mice. PLG did not alter the whole brain levels of morphine, nor did it alter the naloxone potency in mice which were not pretreated with 30 mg/kg morphine. In mice treated with 100 mg/kg morphine or implanted with 50 mg morphine pellets for 24 or 72 h, the amount of naloxone required to induce jumping was not altered by PLG. However, PLG treatment did increase the hypothermia and body weight loss seen after naloxone-induced withdrawal. Administration of PLG to morphine-dependent mice 1 h prior to naloxone did not modify the resultant hypothermia or body weight loss. These results indicate that PLG facilitated the development of morphine tolerance and dependence.     

Study of morphine-induced dependence in gonadectomized male and female mice

In this study we evaluated the effects of sex difference and also sex hormones on the naloxone-precipitated morphine withdrawal in both orchidectomized (ORC) male and ovariectomized (OVX) female mice. Morphine (50, 50 and 75 mg/kg/day for 4 days, s.c.) was administered to animals and at 5th day naloxone (4 mg/kg, i.p.)-precipitated morphine withdrawal signs, jumpings and the percentage of weight loss, were measured. There was no significant alteration in withdrawal jumpings between male and female mice, though weight loss was significantly higher in male ones. Jumpings was significantly lower in both OVX and ORC mice and percentage of weight loss was significantly higher in OVX mice than corresponding non-operated or sham animals. In OVX mice, E₂V (10 mg/kg, s.c.) increased number of jumpings and decreased percentage of weight loss. Progesterone (25 mg/kg, s.c.) had no effect on jumpings, whereas it decreased weight loss in OVX mice. Testosterone (2.5 mg/kg, s.c.) increased jumpings in ORC mice while it had no effect on percentage of weight loss. Our results demonstrated that sex hormones could play a role in the morphine withdrawal syndrome in both ORC male and OVX female mice.     

Reduction of morphine dependence and potentiation of analgesia by chronic co-administration of nifedipine

Nifedipine, 5 mg/kg IP, potentiated the morphine-induced analgesia measured in the hot-plate, but not in the tail-flick test. Further experiments were carried out using the hot-plate test only. Pretreatment with nifedipine partially restores the analgesic action of morphine in morphine-tolerant rats. Co-administration of nifedipine with morphine in a chronic experiment did not prevent the loss of morphine efficiency (an increase in latency of 44% was not significant) and did not prevent the debilitating effect of chronic morphine administration reflected by an inhibition of the body weight gain, but prevented naloxone-induced withdrawal syndrome (quantified by counting head shakes) in the test carried out 24 h after the injection of nifedipine, when the drug did not affect morphine analgesia. Chronic treatment with either morphine or nifedipine did not produce a significant increase in the density of [³H] naloxone or [³H]prazosin binding sites in the cortex and in the rest of the brain (measured 24 h after the last dose), but the combined treatment resulted in a significant increase in the cortical [³H]prazosin binding site density. The present results suggest that opiate tolerance and physical dependence may be separated by coadministration of nifedipine and suggest that the combined chronic treatment with morphine and nifedipine may increase the efficacy of morphine during chronic treatment and prevent development of abstinence.     

Morphine analgesia suppresses tumor growth and metastasis in a mouse model of cancer pain produced by orthotopic tumor inoculation

The present study was conducted to clarify whether relief from cancer pain by morphine would suppress tumor growth and metastasis. When given orthotopic inoculation of B16-BL6 melanoma cells into the hind paw, C57BL/6 mice showed moderate and marked hyperalgesia on days 7-10 and from day 14 post-inoculation, respectively. The volume of inoculated hind paw was increased exponentially as a function of time from day 8 post-inoculation, a phenomena being due to melanoma growth. Lung metastasis was apparent after day 12 post-inoculation. On day 16 post-inoculation, the hyperalgesia was completely inhibited by subcutaneous injection of morphine hydrochloride (5 and 10 mg/kg). The tumor growth and lung metastasis were markedly inhibited by repeated administration of morphine (5 and 10 mg/kg daily for 6 days) and also by the neurectomy of sciatic nerve innervating the inoculated region. The results suggest that relief from cancer pain by morphine inhibits tumor growth and metastasis.     

A genetic analysis of morphine-induced running and analgesia in the mouse

A genetic analysis of morphine-induced analgesia and activity was conducted in mice belonging to the strains BALB/cJ, C57BL/6J, DBA/2J and to their F1 and backcross progenies. The results support previous findings showing that a negative correlation is evident between these two behavioral measures and support that their mode of inheritance is characterized by dominance or partial dominance. The biometric analysis conducted on the parental, F1 hybrid and backcross populations indicates very clearly that the effects of morphine are genetically determined.     

Effects of (-)-epigallocatechin gallate on the development of morphine-induced physical dependence

Among the various nervous systems and signaling components involved in the development of morphine withdrawal symptoms, sensitization of the brain dopaminergic nervous system and an increase in the cAMP levels in the locus coeruleus are believed to be the most important cellular events. This study tested the effects of (-)-epigallocatechin gallate (EGCG), a major compound of green tea, on the development of morphine-induced withdrawal symptoms. All the naloxone-precipitated withdrawal symptoms in morphine-dependent animals were inhibited by an EGCG pretreatment in a dose-dependent manner, being forepaw tremor, rearing, teeth chattering, urination, and wet dog shake were more sensitive than jumping and ptosis. In addition, EGCG showed moderate inhibitory effects on the morphine-induced increase in the cAMP levels in the locus coeruleus at 100 mg/kg and the signaling of the dopamine D2 receptor at 100 microM. Effects of EGCG on the sequestration of D2 receptor were inconclusive. These results suggest that EGCG has strong pharmacological activity against the development of morphine dependence, which can be partly explained by its inhibitory effects on the morphine-induced increase in the cAMP levels in the locus coeruleus and the signaling of the dopamine D2 receptor.     

The effects of receptor selective opioid peptides on morphine-induced analgesia

Utilizing the mouse tail-flick assay, four opioid peptides, which have been reported to be selective for either μ- or δ-opioid receptors, were examined for their analgesic potency and for their ability to modify morphine-induced analgesia. [D-Ala²,D-Leu⁵]enkephalin and [D-Ser²,Thr⁶]leucine-enkephalin, putative δ-receptor selective peptides, produced a potent analgesic response and at subanalgesic doses potentiated morphine-induced analgesia. Morphiceptin and [D-Ala²,Pro⁵]enkephalinamide, putative μ-receptor selective peptides, were similarly found to produce analgesia. However, in contrast to the δ-receptor selective peptides, three μ-receptor selective peptides were unable to alter the potency of morphine. Thus, it would appear that the potentiation of morphine analgesia is a unique property of δ-receptor selective peptides.     

Influence of hemicholinium (HC-3) on morphine analgesia, tolerance, physical dependence and on brain acetylcholine

Administration of HC-3 intracerebrally at a dose which reduced brain acetylcholine (ACh) without any change in choline (Ch) levels antagonized morphine antinociception slightly as measured by inhibition of the tail-flick response, in both naive mice and in mice rendered tolerant to and dependent on morphine by pellet implantation. However, the development of tolerance to morphine and of dependence on morphine were not affected by HC-3. Although naloxone precipitated withdrawal jumping was enhanced irrespective of whether the HC-3 was administered before or after the dependence on morphine had developed, body weight loss during abrupt withdrawal was unaffected by HC-3. The results indicate that although some of the acute and withdrawal effects of morphine may be associated either directly or indirectly with acetylcholine, these actions do not appear to be the primary process responsible for initiating the development of tolerance and dependence.     

Influence of prazosin and clonidine on morphine analgesia,tolerance and withdrawal in mice

Rapid development of tolerance and dependence limits the usefulness of morphine in long-term treatment. We examined the effects of clonidine (₂-adrenoceptor agonist) and prazosin (₁-adrenoceptor antagonist) on morphine analgesia, tolerance and withdrawal. Morphine tolerance was induced using a 3-day cumulative twice-daily dosing regimen with s.c. doses up to 120 mg/kg. Tolerance was assessed on day 4, as loss of the antinociceptive effect of a test dose of morphine (5 mg/kg). After 10 h, morphine withdrawal was precipitated with naloxone (1 mg/kg). Prazosin had no analgesic effect alone but dose-dependently potentiated morphine analgesia in morphine-naive mice. Another ₁-adrenoceptor antagonist, corynanthine, had similar effects. Prazosin also increased the analgesic potency of the morphine test dose in morphine-tolerant mice. Naloxone-precipitated vertical jumping was not affected, but weight loss was reduced by prazosin. Acutely administered clonidine potentiated morphine analgesia and alleviated opioid withdrawal signs, as expected. We conclude that in addition to the already established involvement of ₂-adrenoceptors in opioid actions, also ₁-adrenoceptors have significant modulatory role in opioid analgesia and withdrawal.     

The interference of some cytostatics on morphine-induced analgesia.

The influence of some cytostatic agents (the antibiotic daunomycin, the polypeptide peptikemio and the nitrosourea derivative BCNU) on the antinociceptive effect of morphine is here investigated. It is demonstrated that daunomycin and peptikemio significantly enhance morphine-induced analgesia, while on the other hand, BCNU is ineffective. Daunomycin neither prevents morphine binding to blood proteins nor facilitates its access to the brain. A role of calcium ions in daunomycin potentiating effect is suggested.