Bradykinin antagonizes morphine-induced analgesia in rats

The intraventricular injection of 5 micrograms of bradykinin or Met-Lys-bradykinin in rats antagonized the increase in nociception threshold induced by morphine (5 micrograms i.c.v. or 10 mg/kg i.p.) in the tail flick test. The effect of the two kinins was prevented by atropine (30 mg/kg i.p.). The results suggest that bradykinin counteracts opiate activity in the central nervous system by enhancing acetylcholine release.     

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.     

Dietary influences on theobromine-induced toxicity in rats

Theobromine-induced toxicity was compared at 8, 16, 21, and/or 28 days in rats given either a semisynthetic diet or a pulverized commercial diet in each of which 0.6 or 0.8% theobromine was incorporated. Rats given the pulverized commercial diet containing theobromine consumed more food and therefore, more theobromine over a 28-day period, and gained more weight than did rats given theobromine incorporated into the semisynthetic diet. Serum theobromine concentrations were significantly higher in rats given 0.8% theobromine in the semisynthetic diet than in rats given 0.8% theobromine in the pulverized commercial diet. Spermatogenic cell degeneration and necrosis in the testes of rats fed 0.8% theobromine in the semisynthetic diet for 16 days seemed to be limited to seminiferous tubular cross sections containing stages X to XIV of spermatogenesis, but after 28 days all tubular cross sections showed extensive spermatogenic cell destruction. No significant pathological changes were observed in the testes of rats fed 0.8% theobromine in the pulverized commercial diet for 21 days; spermatogenic cell degeneration and necrosis and multinucleate cell formation were seen after 28 days in seminiferous tubular cross sections containing the early stages of spermatogenesis, but sections containing stages X to XIV were spared or were much less involved. Atrophy of the thymus gland occurred earlier than testicular damage on each respective dietary regimen containing theobromine and was more severe in rats given theobromine in the semisynthetic diet.     

Ovarian steroids and modulation of morphine-induced analgesia and catalepsy in female rats

The effects of dantrolene sodium on the spontaneous and oxytocin-induced contraction of guinea-pig uterus were studied in vitro. Dantrolene reversibly increased the spontaneous contraction frequency of guinea-pig uterus. The effect was not dose-related and was not antagonized by atropine, methysergide or indomethacin. Dantrolene dose dependently and reversibly reduced the contractile responses of guinea-pig uterus to oxytocin. The varying effects of dantrolene on the uterus probably involve inhibition of calcium movement at more than one site of the muscle.     

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.     

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.     

Spinal effect of a neuropeptide FF analogue on hyperalgesia and morphine-induced analgesia in mononeuropathic and diabetic rats.

1DMe, a neuropeptide FF (NPFF) analogue, has been shown to produce antinociception and to enhance morphine analgesia in rats after intrathecal administration. To determine whether 1DMe could correct hyperalgesia and restore morphine efficacy in mononeuropathic (MN) and diabetic (D) rats we examined the spinal effect of 1DMe in MN and D rats without and after spinal blockade of mu- and delta-opioid receptors with CTOP and naltrindole, respectively. The influence of 1DMe on morphine-induced antinociception was assessed in the two models using isobolographic analysis. Whereas 1DMe intrathecally injected (0.1, 1, 7.5 microg rat(-1)) was ineffective in normal (N) rats, it suppressed mechanical hyperalgesia (decrease in paw pressure-induced vocalisation thresholds) in both MN and D rats. This effect was completely cancelled by CTOP (10 microg rat(-1)) and naltrindole (1 microg rat(-1)) suggesting that it requires the simultaneous availability of mu- and delta-opioid receptors. The combinations of morphine: 1DMe (80.6:19.4% and 99.8:0.2%, in MN and D rats, respectively) followed by isobolographic analysis, showed a superadditive interaction, relative to the antinociceptive effect of single doses, in D rats only. In N rats, the combination of morphine: 1DMe (0.5 mg kg(-1), i.v.: 1 microg rat(-1), i.t., ineffective doses) resulted in a weak short-lasting antinociceptive effect. These results show a different efficacy of 1DMe according to the pain model used, suggesting that the pro-opioid effects of the NPFF in neuropathic pain are only weak, which should contribute to hyperalgesia and to the impaired efficacy of morphine.     

Caffeine interferes with morphine-induced hyperactivity but not analgesia

In C57BL/6 mice caffeine antagonized morphine-induced hyperactivity. This effect was most evident when caffeine was used in doses that slightly increased locomotor activity. Given at the same dose caffeine did not affect morphine-induced analgesia. Two possibilities of explanation of this effect are discussed: action of caffeine on dopaminergic mechanisms responsible for morphine-induced running fit through its effect on cyclic AMP level, and a direct action of caffeine on delta opiate receptors involved in the stimulatory effect of morphine.     

Effects of some adenosine analogs on morphine-induced analgesia and tolerance

1. The analogs of adenosine D- and L-phenylisopropyladenosine (D- and L-PIA) and chloroadenosine (CADO) induced analgesia in mice (hot-plate test). 2. The antinociceptive effects of the three adenosine agonists were antagonized by caffeine but were unaffected by naloxone. 3. Morphine-induced antinociception was increased by pretreatment with adenosine agonists. 4. Whereas CADO significantly attenuated the induction of morphine tolerance, D- and L-PIA did not affect the process.     

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.     

Differential effects of opiate agonists-antagonists on morphine-induced hyperexcitability and analgesia in mice

The effects of two opiate agonists-antagonists, butorphanol (4.0 and 8.0 mg/kg) and buprenorphine (0.1 and 1.0 mg/kg), were assessed on locomotor activity and analgesia in DBA/2 and C57BL/6 mice. Diferrent behavioral effects were evident in these strains, which might becharacterized by different reactions to the effects of opiates and by differences in endorphin distributions and opiate receptor populations. In particular, buprenorphine acted as an agonist-antagonist to morphine in both strains while a dissociation of buturphanol effects was evident, depending on the strain considered. The clinical implications of these findings are discussed.     

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.     

Calcium channel involvement in magnetic field inhibition of morphine-induced analgesia

Summary An exposure for 60 min to a weak 0.5 Hz rotating magnetic field significantly reduced the day-time analgesic effects of morphine in male mice. The dihydropyridine (DHP) calcium channel antagonists diltiazem and nifedipine and the non-DHP antagonist verapamil, as well as the inorganic calcium channel blockers, La³⁺ and Co²⁺, differentially reduced, while the DHP calcium channel agonist, BAY K 8644, enhanced the inhibitory effects of the magnetic stimuli. In a similar manner, though to a lesser degree, the calcium channel antagonists and agonist, increased and decreased, respectively, the inhibitory effects of intracerebroventricular administrations of Ca²⁺ on morphine-induced analgesia. The calcium channel antagonists and agonists had no significant effects on naloxone-mediated reductions of morphine-induced analgesia. These results suggest that exposure to magnetic stimuli affects the functioning of calcium channels and the distribution of calcium ions, thereby, altering the effects of opiates. Send offprint requests to M. Kavaliers     

Intracerebroventricular administration of angiotensin II attenuates morphine-induced analgesia in mice

The central effect of angiotensin II on the analgesic action of morphine in mice was investigated using the tail-pinch and hot plate tests. Angiotensin II (0.1-10 pmol), given intracerebroventricularly (i.c.v.), had no effect on the nociceptive sensitivity but did produce a dose-dependent attenuation of the morphine-induced analgesia. A specific angiotensin II antagonist, Saralasin (1 pmol), which in itself had no analgesic effect, significantly potentiated the morphine-induced analgesia. These results suggest that angiotensin II probably plays the physiological role of an anti-opioid substance in pain-modulating systems in the brain.     

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。     

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.     

Agmatine inhibits morphine-induced drug discrimination in rats

Our previous studies have shown that agmatine inhibited morphine-induced conditioned place preference and locomotor sensitization in rats. In the present study, we further investigated the effects of agmatine on the discriminative stimulating effects produced by morphine in rats. Agmatine, at the dose range of 10-80 mg/kg (i.g.), neither induced drug discrimination, nor substituted for morphine stimulus in rats that were previously treated with morphine, suggesting that agmatine itself has no psychomotor-stimulating potential. However, pretreatment with agmatine (40, 80 mg/kg, i.g.) significantly inhibited the acquisition, but not expression, of morphine-induced drug discrimination as assessed by the correct nose-poke response. Further, chronic administration of agmatine (40, 80 mg/kg/dayx12 days, i.g., 25 min prior to morphine) also significantly accelerated the extinction of the discrimination induced by morphine. These data suggest that agmatine inhibits the acquisition and accelerates the extinction of morphine-induced discrimination, supporting possible use of agmatine in the treatment of opioid dependence.     

The effect of dopaminergic modifiers on morphine-induced analgesia and respiratory depression.

The influences of the dopaminergic system on morphine-induced analgesia and respiratory depression were compared using modulators of dopaminergic activity. Blockade of dopaminergic receptors by haloperidol or pimozide produced a potentiation of morphine analgesia, while stimulation of dopaminergic activity by L-dopa methyl ester inhibited morphine analgesia. Morphine-induced depression of respiratory rate was potentiated by haloperidol and inhibited by pimozide or L-dopa methyl ester. These results suggest that the dopaminergic system plays a modulating role in morphine-induced analgesia, but not in morphine-induced respiratory depression.     

Tolerance develops to spinal morphine analgesia but not morphine-induced convulsions

Administration of morphine into the spinal intrathecal (i.t.) space produced dose-dependent analgesia in the mouse. At higher doses i.t. morphine induced seizures of the hindlimbs. Mice treated chronically with morphine (75 mg pellet, s.c.) for 72 h were tolerant to the analgesic effects of i.t. morphine, but not to the proconvulsant action. Spinal morphine analgesia was attenuated by naloxone, whereas i.t. morphine-induced seizures were not. These results indicate that spinal opioid receptors mediate analgesia but not seizures following i.t. morphine treatment in the mouse.