Influence of sertraline on the antinociceptive effect of morphine, metamizol and indomethacin in mice

Interaction between analgesic and various psychotropic drugs constitute a subject of many research investigations. Literature data considering this issue are often inconsistent. Sertraline is one of the most potent drugs in the family of selective serotonine reuptake inhibitors (SSRIs). The influence of sertraline (5 mg/kg) on antinociceptive effect of morphine (10 mg/kg), metamizol (500 mg/kg) and indomethacin (10 mg/kg or 1.4 mg/kg) was investigated in a mouse model using the tail-flick and hot-plate tests. All drugs were injected intraperitoneally. Sertraline was administered to mice 30 min before applying the analgesic drugs. Measurement of nociception was performed within 2 h after sertraline administration. The research studies were futher conducted with multiple (14 days) drug dosage. Sertraline after single dose increased the antinociceptive effect of morphine (in the hot-plate test) and metamizol and indomethacin (only in the tail-flick test). Sertraline after 14 day administration decreased analgesic effect of morphine (only in the hot-plate test). Sertraline applied for 14 days increased the antinociceptive effect of indomethacin. Sertraline alone after multiple doses increased pain reaction time. The results of experiments suggest the role of sertraline in nociception and possibility of interaction between sertraline and analgesic drugs.     

Effect of diazepam and midazolam on the antinociceptive effect of morphine, metamizol and indomethacin in mice

The influence of midazolam and diazepam on antinociceptive effect of morphine (10 mg/kg), metamizol (500 mg/kg) and indomethacin (10 mg/kg) was investigated in a mouse model using the tail-flick and hot-plate tests. All drugs were injected intraperitoneally. Benzodiazepines were administered to mice 30 min before applying the analgesic drugs. Measurement of nociception was performed within 2 h after benzodiazepine administration. Diazepam at doses of 0.25 mg/kg and 2.5 mg/kg injected with morphine was found to decrease the antinociceptive effect of morphine. Similarly, diazepam decreased the antinociceptive effect of metamizol (only in the tail-flick test) and indomethacin. Midazolam used at doses of 1.25 mg/kg and 2.5 mg/kg decreased the antinociceptive effect of morphine, metamizol (only in the tail-flick test) and indomethacin.     

Influence of felbamate on the antinociceptive action of morphine, metamizol and indomethacin in mice

The influence of felbamate (200 mg/kg or 50 mg/kg) on antinociceptive effect of morphine (10 mg/kg), metamizol (500 mg/kg) and indomethacin (10 mg/kg or 1.4 mg/kg) was investigated in a mouse model using the hot-plate test. All drugs were injected intraperitoneally. Felbamate was administered to mice 30 min before applying the analgesic drugs. Measurement of nociception was performed within 2 h after felbamate administration. The research studies were further conducted with a multiple (10 days) drug dosage. Felbamate in the dose of 200 mg/kg significantly increases the analgesic effect of morphine and weakens the effect of metamizol and indomethacin. Multiple administration of felbamate does not affect the activity of morphine and metamizol, but decreases analgesic effect of indomethacin.     

Influence of mianserin on the antinociceptive effect of morphine, metamizol and indomethacin in mice.

The influence of mianserin (5 or 3.6mgkg(-1)) on antinociceptive effect of morphine (10mgkg(-1)), metamizol (500mgkg(-1)) and indomethacin (10 or 1.4mgkg(-1)) was investigated in a mouse model using the tail-flick and hot-plate tests. All drugs were injected intraperitoneally (i.p.). Mianserin was administered to mice 30min before applying the analgesic drugs. Measurement of nociception was performed within 2h after mianserin administration. The study was further conducted for 14 days with multiple drug doses. The results indicate that mianserin in a single dose increased the antinociceptive effect of metamizol (in the hot-plate and tail-flick tests) and indomethacin (only in the tail-flick test). Mianserin administered for 14 days together with metamizol increased the analgesic effect of the latter drug (in the hot-plate and tail-flick tests). Mianserin applied for 14 days increased the antinociceptive effect of indomethacin (in the tail-flick test).     

Influence of tiagabine on the antinociceptive action of morphine, metamizole and indomethacin in mice

The influence of tiagabine at a dose of 3.2 mg/kg (single administration) and at a dose of 1.2 mg/kg (multiple administration - 10 days) on the antinociceptive effect of morphine (10 mg/kg), metamizole (500 mg/kg) and indomethacin (10 mg/kg - single dose and 1.4 mg/kg - multiple doses) was investigated in mice using the hot-plate and tail-flick tests. All drugs were injected intraperitoneally. Tiagabine was administered to mice 30 min before the analgesic drugs. Measurement of the reaction to a noxious stimulus was performed 60, 90 and 120 min after administration of tiagabine. The study was further conducted for 10 days with repeated drug doses. Tiagabine and morphine administered in single doses demonstrate an additive antinociceptive effect in the hot-plate test and a slightly synergistic effect in the tail-flick test. A single administration of tiagabine slightly increased the antinoceptive action of metamizole and indomethacin in both tests, but that effect is less pronounced than the antinociceptive action of tiagabine alone. Repeated administration of tiagabine with morphine abolishes the tolerance to morphine analgesia. Both single and repeated administration of tiagabine alone exerted the antinociceptive effect in the hot-plate test.     

Effect of citalopram and buspirone on the antinociceptive action of analgesic drugs.

The influence of citalopram (20 mg/kg i.p.) and buspirone (3 mg/kg i.p.) on analgesic effects of morphine (10 mg/kg i.p.), metamizole (500 mg/kg i.p.) and indomethacin (10 mg/kg) was studied with tail-flick and hot-plate tests on mice. The research studies were further conducted with multiple (14 days) drug dosage. The results indicate that citalopram and buspirone decrease analgesic effects of morphine, metamizole and indomethacin. This mode of action is more pronounced in case of a single dose than after multiple doses.     

Analgesic efficacy of the combination metamizol+morphine after subchronic treatment in rats

In the present study, the analgesic efficacy and the possible development of tolerance produced by the combination metamizol+morphine (562.3:5.6 mg/kg) during subchronic treatment (6 and 12 days) in arthritic rats using the PIFIR model was evaluated. This combination of metamizol+morphine produced the maximum analgesic efficacy (AUC_E = 353.4 ± 24.7 au) when compared with morphine 5.6 mg/kg (AUC_E = 196.6 ± 35.3 au), metamizol 562.3 mg/kg (AUC_E = 262.8 ± 10.2 au), and morphine 10 mg/kg (AUC_E = 316.6 ± 31.0 au) given in a single dose. The results were essentially the same when the combination was administered for 6 (AUC_E = 325.4 ± 13.1 au) or 12 days (AUC_E = 354.5 ± 9.6 au). In addition, the duration of the effect was longer when the combination metamizol+morphine was administered either in single or subchronic treatment. Development of tolerance to the analgesic effect was observed after 6 and 12 days of morphine administration. However, the analgesic effect produced by the metamizol+morphine combination remained constant (near 100%) during both subchronic treatments. The present data demonstrate that metamizol significantly attenuates the development of tolerance to morphine. The mechanism involved in this effect of metamizol remains to be determined. Drug Dev. Res. 51:260–267, 2000. © 2001 Wiley‐Liss, Inc.     

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。     

Gabapentin enhances the analgesic response to morphine in acute model of pain in male rats

Whenever opioids as drug of choice result in inadequate analgesia, the combinational therapy would be the solution. In this study the co-administration of gabapentin with morphine is evaluated in acute model of pain. Therefore the antinociceptive effect of gabapentin (30 or 90 mg/kg, s.c.) and morphine (0.5, 1 or 3 mg/kg, s.c.) alone or in combination were measured by tail-flick test in intact adult male rats. Control rats received normal saline. Tail-flick latency time and Area Under Curve (AUC), as antinociception index were calculated for each groups. There was not any significant difference between the antinociceptive response of 0.5 mg/kg morphine and 30 mg/kg gabapentin as compared to controls, but co-administration of these subanalgesic doses increased significantly AUC as compared to morphine alone. The co-administration of gabapentin with analgesic doses of 1 and 3 mg/kg morphine had also increased significantly AUC. Therefore gabapentin enhanced the antinociceptive effect of both analgesic and subanalgesic doses of morphine in a dose dependent manner. In conclusion co-administration of gabapentin with low doses of morphine produced therapeutic analgesia which could have important clinical application.     

The effect of ciprofloxacin and gentamicin on spinal morphine-induced antinociception in rats

This paper investigates the possible antinociceptive effect of systemically administered ciprofloxacin and gentamicin and its influence on intrathecal morphine-induced antinociception. Using thermal nociceptive tests (hot-plate test and tail-flick test) and a motor function test (catalepsy test) in male Sprague-Dawley rats (n=5-9/dose), the following observations were made: ciprofloxacin administered intraperitoneally in the dose range 4-64 mg/kg demonstrated a modest antinociceptive effect in both nociceptive tests. Solvent of ciprofloxacin (intraperitoneally) and saline (intraperitoneally), given as a control, showed no effect. Gentamicin, administered at a dose of 0.1-4 mg/kg intraperitoneally, demonstrated a significant (P<0.05) antinociceptive effect in the tail-flick test but not in the hot-plate test. However, opioid antagonists caused no significant change in the antibiotics. Furthermore, ciprofloxacin intraperitoneally produced a significant left-shift in the hot-plate test (ED50 saline-morphine=2.86 [CI 95%: 2.2, 4.32]microg; ED50 ciprofloxacin-morphine=0.87 (CI 95% 0.68, 1.21) microg, P<0.05) and in the tail-flick test (ED50 saline-morphine=1.98 (CI 95%: 1.21, 2.84) microg; ED50 ciprofloxacin-morphine=0.37 (CI 95%: 0.23, 0.44) microg; P<0.05) for intrathecal morphine-induced antinociception. From a comparison of these data with the predicted ciprofloxacin-morphine value (hot-plate test: 1.61 (CI 95%: 1.18, 2.51]microg; tail-flick test: 0.82 (CI 95%: 0.52, 1.92) microg) we estimate that ciprofloxacin and morphine produce at least additive effects (P>0.05). This was reversed with intraperitoneal naloxone (P<0.05). Gentamicin intraperitoneally did not influence the antinociception achieved with intrathecal administration of morphine (hot-plate test: ED50 gentamicin-morphine=2.71 (CI 95%: 2.35; 3.2) microg; tail-flick test: ED50 gentamicin-morphine=2.43 (CI 95%: 1.58; 5.22]microg; P>0.05). These data show that intraperitoneal administration of ciprofloxacin and gentamicin produces a modest antinociceptive effect in the hot-plate test and tail-flick test. Ciprofloxacin, but not gentamicin, can interact at least additively to increased naloxone-reversible morphine intrathecal antinociception. Differences in the ability to penetrate the blood-brain barrier between the two antibiotics could explain the lack of effect from gentamicin in the hot plate and on morphine-induced antinociception.     

The antinociceptive effects of 3,4-methylenedioxymethamphetamine (MDMA) in the rat

The antinociceptive effects of MDMA and morphine were examined in rats using the tail-flick and hot-plate analgesiometric tests. MDMA, in the dose range of 1.5-6.0 mg/kg IP, produced a dose-dependent elevation in hot-plate latency, but did not elevate tail-flick latency. In contrast, morphine (2-8 mg/kg, IP) produced analgesia on both the tail-flick and hot-plate tests in a dose-dependent manner. Neither the opiate antagonist naltrexone nor the adrenoceptor antagonist phentolamine effectively attenuated MDMA-induced analgesia. Conversely, the serotonin antagonist methysergide significantly reversed the analgesic effects of MDMA on the hot-plate test. These findings suggest that the antinociceptive effects of MDMA are serotonergically mediated. Furthermore, the results verify earlier findings describing the test-specific effects of serotonin-induced pain modulation.     

Potentiation of morphine analgesia in rats given a single exposure to restraint stress immobilization.

Rats exposed to restraint stress and injected with morphine show significantly greater increases in tail-flick latency compared to unstressed rats. However, it is not necessary for rats to be restrained at the time of testing to elicit a potentiated analgesic response to morphine. We reported recently that analgesia induced by 4.0 mg/kg morphine was significantly potentiated in rats that had been restrained for only 1 h at 24 h prior to testing. One purpose of the present study was to extend this observation by determining the ability of a single exposure to restraint stress to potentiate dose-dependently morphine (0.0, 2.0, 4.0, and 8.0 mg/kg)-induced analgesia in the tail-flick test. A second purpose was to assess the generality of the phenomenon by determining whether prior restraint would potentiate the analgesic effect of morphine in another common analgesic assay, the hot-plate test. Dose- and time-course (20-120 min) curves for morphine were generated in rats exposed to one of two treatments: no restraint stress (NS) and a single exposure to 1 h of restraint (RS). Rats subjected to 1 h of restraint and tested 24 h later displayed significant time- and dose-dependent potentiation (1.3-2.0-fold) of morphine-induced analgesia compared to unstressed rats in both the tail-flick and hot-plate tests. These results demonstrate that a single period of restraint is sufficient to activate the mechanisms responsible for potentiation of morphine-induced analgesia and that the degree to which stress modified morphine's analgesia can be demonstrated using both the tail-flick and hot-plate assays.     

Analgesic effects of lornoxicam in formalin-induced inflammation]

Peroral administration of lornoxicam, a new representative of the class of oxicams, in a total dose of 2-16 mg/kg produced a dose-dependent analgesic effect in rats with formalin-induced tail inflammation, as confirmed by the tail-flick and hot-plate tests. The maximum analgesic effect of lornoxicam during the formalin-induced edema development was observed upon a three-fold drug administration by the scheme 1/2, 1/4, 1/4 of the total dose (8-16 mg/kg, p.o.) with a 3 h interval prior to formalin injection into the rat tail base. Validity of using the tail-flick and hot-plate methods for evaluation of the analgesic effect of NSAID is discussed.     

The effect of adenosine receptor agonists on analgesic effects of morphine

The effect of adenosine, S-phenylisopropyladenosine (S-PIA) and dipyridamole (an adenosine reuptake inhibitor) on the analgesic action of morphine in mice and rats was investigated in the hot-plate (56 degrees C) and tail immersion (52 degrees C) tests. Adenosine, 50 and 100 mg/kg, induced analgesia in mice and rats in the hot-plate test and potentiated the action of morphine (particularly in mice). The analgesic effects of adenosine were completely abolished by caffeine (10 mg/kg in mice and rats), and partially inhibited by naloxone (1 mg/kg, only in mice). S-PIA given alone (0.6 mg/kg) produced in mice some analgesic effect in the hot-plate test: the effect was abolished by caffeine and partially by naloxone. The effect of S-PIA on the action of morphine depends on the dose and the animal species. Dipyridamole alone did not affect the reactivity of animals in tests for analgesia, but potentiated the action of morphine.     

Serotonin receptor antagonists induce hyperalgesia without preventing morphine antinociception

5-Hydroxytryptamine (5-HT) receptor blockade by administration of mianserin (1 mg/kg) or metergoline (0.25 mg/kg) shortened the response latencies of rats in the hot-plate (hind-paw lick response) and tail-flick tests, but did not consistently attenuate the antinociceptive effect of morphine (1.25--5.0 mg/kg). Injection of the opiate receptor antagonist naloxone (1 mg/kg) did not change tail-flick response latencies and did not interfere with the antinociceptive action of the 5-HT receptor agonist 5-methoxy-N,N-dimethyltryptamine (5-MeODMT). The antinociceptive effect of morphine was reduced in chronically spinal rats, although significant increases in tail-flick latencies were observed after 2.5 and 5.0 mg/kg. Concomitant administration of 5-MeODMT failed to restore the effect of morphine in spinal rats. In the hot-plate test, morphine did not reliably prolong latencies to forepaw lick, indicating that this response is not a useful measure of pain sensitivity. The results suggest that different mechanisms underlie the analgesia induced by systemic administration of morphine and 5-HT mediated tonic inhibition of nociception.     

Evidence for the involvement of central opioidergic systems in L-tyrosine methyl ester-induced analgesia in the rat

Intraperitoneal administration of L-tyrosine (used as methyl ester HCl) produced dose-dependent analgesia in male Sprague-Dawley rats as measured by the tail-flick test. The maximal analgesic response was obtained with 200 mg/kg dose of tyrosine. Administration of morphine also produced a dose-dependent analgesic response. Tyrosine in doses of 50 mg/kg or higher potentiated morphine-induced analgesia. The analgesic response of tyrosine (200 mg/kg) was antagonized by naloxone (1 mg/kg), an opiate antagonist. Subcutaneous administration of methyl naltrexone bromide (MRZ 2663 BR, 1 and 10 mg/kg) had no effect on tyrosine-induced analgesia. Intracerebroventricular injection of MRZ 2663 BR (1 and 10 micrograms/rat) effectively blocked tyrosine-induced analgesia. It is concluded that tyrosine-induced analgesia and its potentiation of analgesic response to morphine may be mediated via either the opiate receptors or activation of endogenous opioidergic systems of central origin.     

Monosodium glutamate and analgesia induced by morphine. Test-specific effects

Neonatal administration of monosodium glutamate (MSG) destroyed perikarya in the arcuate nucleus and median eminence, including those that contain met-enkephalin and beta-endorphin and it increased the density of opiate receptors in the midbrain. Treatment with glutamate decreased the analgesic response on the jump test following a 10 mg/kg dose of morphine, yet increased the analgesic response on the hot-plate test following 1 mg/kg dose of morphine. The present study demonstrated that changes in morphine-induced analgesia induced by glutamate varied as functions of the pain test and of gender. While males treated with glutamate displayed attenuated analgesia induced by morphine (2.5-15 mg/kg) on the jump test, jump thresholds of females treated with glutamate were potentiated after a 10 mg/kg dose of morphine and attenuated after a 15 mg/kg dose of morphine, relative to controls. In contrast, analgesia on the hot-plate test was potentiated in animals of both genders treated with glutamate after all doses of morphine. Changes in tolerance to morphine induced by glutamate also depended on the pain test and gender. While the peak analgesic response on the jump test did not occur until the fifth injection of morphine in all rats treated with glutamate, tolerance on the jump test was subsequently retarded in males treated with glutamate and accelerated in glutamate-treated females. Tolerance on the hot-palate test appeared not to be consistently affected by treatment with glutamate. Morphine-induced hyperthermia was initially decreased in rats treated with glutamate, but subsequently decreased in glutamate-treated males and increased in glutamate-treated females.(ABSTRACT TRUNCATED AT 250 WORDS)     

Corticosteroid effects on morphine-induced antinociception as a function of two types of corticosteroid receptors in brain

The antinociceptive effect of parenterally and intracerebroventricularly injected morphine and beta-endorphin in adrenalectomized rats and in adrenalectomized rats treated with adrenal steroids was examined employing the hot-plate method. (1) Adrenalectomy sensitized the rats to an analgesic effect of morphine and beta-endorphin. (2) Replacement therapy (chronic and acute) with corticosterone, dexamethasone or RU 28362 (glucocorticoid receptor agonist) effectively reversed the increase in the sensitivity to the analgesic effect of peripherally injected morphine (5 mg/kg i.p.) induced by adrenalectomy to the level of sham-operated animals. Glucocorticosteroids administered to non-adrenalectomized rats did not change the sensitivity to morphine. (3) Corticosterone had a biphasic, dose-dependent effect; the most significant attenuation of the hypersensitivity to morphine-induced antinociception in adrenalectomized rats was achieved after 0.01 mg and after 10 mg (per kg b.w.). Doses of corticosterone of 0.005 mg/kg and in a range of 0.05-0.30 mg/kg were ineffective. (4) Corticosterone in a dose of 0.01 mg/kg (s.c.) had suppressant effects on the adrenalectomy-induced increase in the sensitivity to antinociception induced by morphine when given prior to morphine (60, 30 and 5 min) as well as after the injection of morphine (before the first and the second testing on the hot-plate, 15 and 5 min, respectively). (5) Intracerebroventricularly (i.c.v.) injected morphine and beta-endorphin also displayed the hypersensitivity to the analgesic effect in adrenalectomized rats which in both cases could be suppressed by 0.01 mg/kg of corticosterone given subcutaneously 5 min prior to administration of the opiate.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of sumatriptan in different models of pain in rats

The effect of sumatriptan in two standard algesimetric tests and in a model of cephalalgia was evaluated in rats. The pain threshold was measured by the hot-plate and the writhing tests; cephalalgia was produced by injecting bradykinin (10 μg in a volume of 10 μl) into a common carotid artery. Sumatriptan was subcutaneously (s.c.) injected at the doses of 4, 8, 24 or 42 mg/kg; morphine (5 or 10 mg/kg s.c.) and indomethacin (5 or 10 mg/kg s.c) were used as standard analgesic drugs. Sumatriptan had no analgesic activity either in the hot-plate test or in the writhing test. On the other hand, at 24 and 42 mg/kg it dose-dependently reduced the response to the intracarotid injection of bradykinin (vocalization and tachypnea), this effect being prevented by the 5-HT_1B receptor antagonist, isamoltane. The 5-HT_1D receptor antagonist BRL15572 prevented the effect of sumatriptan on bradykinin-induced tachypnea, but not the effect of sumatriptan on bradykinin-induced vocalization. These data demonstrate that sumatriptan is significantly effective in a reliable animal model of cephalalgia, while having no systemic analgesic activity.