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.     

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 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.     

Modification of antinociceptive action of morphine by dopamine agonist and antagonist in mice

A marked potentiation of the antinociceptive action of morphine was produced by haloperidol, but apomorphine had no effect on the antinociceptive action of morphine in acute experiments. Following chronic treatment with haloperidol, the antinociceptive action of morphine was significantly suppressed by apomorphine, and apomorphine shifted the dose-response curve of morphine to the right and increased the ED50 value of morphine by 2.3-fold. These results suggest that the suppressive action of apomorphine on the antinociceptive effect of morphine in chronic haloperidol-treated mice may be due to an increased sensitivity of post-synaptic dopaminergic receptors to apomorphine.     

The effect of 6-hydroxydopamine on the antinociceptive action of morphine

The role of brain catecholamines in the antinociceptive action of morphine was investigated. Intraventricular 6-hydroxydopamine which depleted brain noradrenaline in the rat had no effect on morphine's antinociceptive action but combined treatment with pargyline and 6-hydroxydopamine to further deplete brain dopamine potentiated morphine's action. It was also shown that when dopamine receptors were blocked, the antinociceptive action of morphine was potentiated whereas alpha- and beta-adrenoceptor antagonists had no effect. 6-Hydroxydopamine had two effects in mice tested on the hot-plate. It produced a hyperalgesia and antagonized the antinociceptive action of morphine. This antagonism of morphine appeared to be the result of the depletion of noradrenaline rather than dopamine. Intraventricular injection of both catecholamines restored the antinociceptive action of morphine in 6-hydroxydopamine-treated mice but dopamine was ineffective in the presence of a dopamine beta-hydroxylase inhibitor. It is suggested that the antinociceptive action of morphine is expressed by noradrenergic neurones in the mouse and by both noradrenergic and dopaminergic neurones in the rat.     

Localization of the antinociceptive action of morphine in primate brain

Microinjections of morphine sulfate (20–40 μg) were made into various subcortical regions of the rhesus monkey brain. The effects of these injections were evaluated on the nociceptive threshold as defined by the shock titration technique. The results of this preliminary investigation indicate that the region of maximal antinociceptive sensitivity to morphine in the primate is the perventricular-periaqueductal gray matter. It is tentatively suggested that morphine lowers that affective tone or the aversive component of pain by its action on the midbrain central gray and periventricular areas - both important projection and integration areas of the extralemniscal somatosensory system.     

Pertussis toxin inhibits the antinociceptive action of morphine in the rat

The influence of pertussis toxin (PTX) injected intracerebroventricularly (i.c.v., 0.5 micrograms) on the analgesic effect induced in the rat by i.c.v. injection of morphine (5 micrograms) was studied. Morphine analgesia was unaffected 24 h after toxin administration, but there was a significant decrease after 6 days. Therefore a PTX-sensitive substrate, probably a guanine nucleotide regulatory protein could be involved in the coupling of opiate receptors to cellular effectors responsible for the expression of the antinociceptive action of morphine.     

The antinociceptive efficacy of morphine, metamizol, or their combination in an experimental rat model with different levels of inflammatory pain

The purpose of this work was to evaluate the antinociceptive efficacy of an optimal morphine and metamizol combination on different levels of nociception (levels I, II, and III) using the “Pain-induced functional impairment model in the rat”. The effect of acetylsalicylic acid was examined as a reference drug at the same levels of nociception. The antinociceptive effects produced by morphine (3.2 mg/kg s.c.) and metamizol (177.8 mg/kg s.c.) were studied either individually or in combination. The antinociceptive efficacies were expressed as either areas under the curve (AUCs), maximum effects as functionality index in percent of the time course, or the antinociceptive effects produced at 2 h after administration. Unlike morphine, the antinociceptive effects of acetylsalicylic acid decreased with increasing intensity of nociception. In summary, the analysis of antinociceptive efficacies produced by the co-administration of these drugs for different levels of nociception revealed that co-administration provided potentiated and better antinociceptive coverage throughout our observation time than did the individual drugs or the expected theoretical sum (using AUC or effects after 2 h). This is the first study to demonstrate that an optimal morphine and metamizol combination is able to produce potentiation of antinociceptive effects during intense pain.     

Relationship between synaptosomal calcium uptake and antinociceptive action of morphine

We studied the relationship between inhibition of 45Ca2+ uptake and the antinociceptive action induced by morphine and effects of papaverine and 1,1-diphenyl-3-piperidinobutanol hydrochloride (Aspaminol) on both these actions of morphine. Addition of these drugs in the incubation medium significantly inhibited glutamate-stimulated synaptosomal 45Ca2+ uptake. The inhibition curves of morphine and Aspaminol on glutamate-stimulated synaptosomal 45Ca2+ uptake were linear, but that of papaverine was not. The inhibition of morphine on synaptosomal 45Ca2+ uptake was reversed by addition of naloxone. The inhibition of synaptosomal 45Ca2+ uptake induced by morphine was increased by the simultaneous addition of Aspaminol, but the inhibition induced by both morphine and papaverine was not increased to more than that by papaverine alone. Since morphine-antinociception was potentiated by Aspaminol and blocked by papaverine, these results support that the inhibition of synaptosomal calcium uptake plays an important role in the production of morphine-antinociception. However, since the inhibition of synaptosomal 45Ca2+ uptake by morphine was less than that by both Aspaminol and papaverine, and papaverine blocked morphine-antinociception, notwithstanding that 10(-4) M of papaverine alone completely inhibited glutamate-stimulated 45Ca2+ uptake into synaptosomes, it may be difficult to account for the antinociceptive action of morphine by the inhibition of 45Ca2+ uptake only.     

On the central sites for the antinociceptive action of morphine and fentanyl

The inhibition by morphine and fentanyl of a nociceptive response, the licking reaction elicited by electrical stimulation of the tooth-pulp, was studied in rabbits. Both drugs were injected into the entire ventricular system, and into its separate parts and morphine was applied to definite brain structures. Spread of the applied drug was examined autoradiographically, using ¹⁴C-labelled morphine. Intraventricular injection of morphine was 500–1000 times more effective than intravenous injection. The onset of action was much slower than after systemic application; this latency is interpreted as being caused by the slow permeation of morphine to the receptor areas in the periventricular structures. Injection into separate parts of the ventricular system did not inhibit the nociceptive reaction when the spread of substance was restricted to one or both lateral ventricles. Inclusion of the third ventricle in the area of distribution resulted in only a slight increase in effectiveness. Application of the drugs into the aqueduct and into the fourth ventricle induced a complete inhibition of the nociceptive reaction. When morphine spread into the surrounding of the cisterna cerebellomedullaris (with exclusion of ventricular system) no effect was observed. Uni- or bilateral microinjection of morphine into various diencephalic and mesencephalic periventricular structures induced a pronounced inhibition of the nociceptive reaction. In at least one part of these experiments, however, morphine may have acted indirectly, by spreading to caudal parts of the ventricular system. The most effective sites of the antinociceptive action of morphine-like substances were situated in the fossa rhomboides and structures near it. Autoradiographical studies showed the sites for the antinociceptive action of morphine to be located in the ventricular wall of these regions at a depth of about 1–2 mm. Diencephalic sites of action were of minor importance, at least when the licking reaction was used as test. The functional structures involved in the drug effects are discussed.     

A local serotonergic component involved in the spinal antinociceptive action of morphine

Participation of opiate, serotonergic and noradrenergic components in the antinociceptive action of intrathecally administered morphine was evaluated by measuring the ability of subcutaneously administered doses of naloxone, methysergide and phentolamine to alter analgesia. Morphine produced a dose-dependent elevation of the tail-flick latency, due exclusively to local spinal actions. For example, 10 nmol of the drug, when administered intrathecally in rats with bilateral lesions of the dorsolateral funiculus, produced an increase in the tail-flick latency, that was similar to that observed in intact animals. Furthermore, morphine was ineffective when administered intracerebroventricularly into the fourth ventricle of intact rats. The spinal antinociceptive action of the opiate was antagonized by naloxone (ID50 = 0.035 mg/kg, s.c.) but was also significantly attenuated by methysergide (ID50 = 4.28 mg/kg, s.c.). Phentolamine was ineffective. Doses of methysergide that were most effective in reversing the spinal action of morphine also produced hyperalgesia when administered alone. On the other hand, when the dorsolateral funiculus was lesioned, the hyperalgesia was no longer observed, yet the antagonist remained effective against morphine. These data suggested that the doses of methysergide needed to antagonize the action of morphine were in the same range as those needed to block the synaptic actions of serotonin (5-HT) released from the tonically-acting, descending pain inhibitory nerves. The results demonstrate that local opiate, as well as serotonergic, mechanisms mediate the antinociceptive action of morphine in the spinal cord. The recruitment of a serotonergic component may be related to an action of opiates within the spinal cord, to cause the release of serotonin from the terminal fields of the spinipetal serotonergic nerves.     

Evidence for the potentiation of the antinociceptive action of morphine by bromocriptine

The effect of bromocriptine on the antinociceptive activity of morphine has been studied in rats and mice. When administered alone, bromocriptine had no effect on the nociceptive state of the animal as reflected by the tail flick latency. However, in conjunction with morphine, bromocriptine significantly potentiated the anti-nociceptive action of morphine in both rats and mice. This potentiation was only observed at specific doses of bromocriptine and was susceptible to blockade by haloperidol. These results indicate that stimulation of at least some dopamine receptor types may modify the antinociceptive effect of morphine.     

8-Phenyltheophylline reverses the antinociceptive action of morphine in the periaqueductal gray.

Morphine was injected into the periaqueductal gray region of the rat and 8-phenyltheophylline, an adenosine receptor antagonist, was injected intrathecally 15 or 30 min later, to determine whether supraspinally-administered morphine activated descending mechanisms to release adenosine (or a nucleotide which is metabolized to adenosine) from the spinal cord. 8-Phenyltheophylline (10 micrograms) reversed the antinociceptive action of morphine in the hot plate but not the tail-flick test. A combination of methysergide/phentolamine (15 micrograms each) reversed the action of morphine in both tests. 8-Phenyltheophylline retained the ability to reverse the action of morphine in the hot plate test in rats pretreated with 6-hydroxydopamine (to induce degeneration of descending noradrenergic pathways) but reversal was no longer observed in rats pretreated with 5,7-dihydroxytryptamine (after pretreatment with desipramine, to induce degeneration of descending serotonergic pathways). These results indicate that a component of the supraspinal antinociceptive action of morphine is due to release of adenosine or nucleotide, within the spinal cord and this release is dependent on intact serotonergic pathways.     

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.     

Effects of adrenalectomy and gonadectomy on the antinociceptive effect of morphine and naloxone antagonism in mice

In the present study the effects of adrenalectomy and gonadectomy on the antinociceptive activity of morphine and its antagonism by naloxone were studied in male and female mice. In the female mice, it was found that adrenalectomy enhanced the antinociceptive activity of morphine by two-fold, while the antinociceptive effects of morphine measured in the presence of naloxone were similar to those of the sham-operated controls. The naloxone potency ratios, expressed as the ratios of morphine ED50s with naloxone to that without naloxone, were increased in adrenalectomised animals. Similar effects were observed in oophorectomised female mice though the influence of oophorectomy on naloxone antagonism was not as effective as adrenalectomy. In animals that were both adrenalectomised and oophorectomised the antinociceptive effect of morphine measured was similar to those animals receiving either operative procedure. However, the naloxone potency ratios determined were between those determined in adrenalectomised mice and oophorectomised animals. In male mice, the effect of adrenalectomy was similar to that observed in the female animals, namely both the antinociceptive activity of morphine and naloxone antagonism were enhanced. Orchidectomy enhanced the antinociceptive effect of morphine but not to the same extent as adrenalectomy. Furthermore, the enhancement of naloxone antagonism was also less than that induced by adrenalectomy. The effects of adrenalectomy and orchidectomy in male mice were similar to those of adrenalectomy alone. These results suggest that steroid hormones are involved in the actions of both morphine and naloxone.     

Effect of diltiazem, nifedipine and verapamil on the antinociceptive action of acetylsalicylic acid in mice

1. Diltiazem, verapamil and nifedipine produced a dose-dependent analgesic response in mice. 2. A fixed oral dose of acetylsalicylic acid increased this analgesic response. 3. Analgesia was maintained when mice were treated chronically with calcium channel blockers alone or when combined with aspirin.     

Studies on the antagonism by raphe lesions of the antinociceptive action of systemic morphine.

In rats, lesions were placed in the dorsal/median raphe (DMR), in the ventral raphe (VR: raphe magnus), in both the dorsal/median and ventral raphe (DMVR) or in the reticular formation (RF). The effect of the lesions on the antinociception and catalepsy produced by 3 doses of morphine (3, 10 and 30 mg/kg) was examined. The lesions had no significant effect on the catalepsy produced by any of the doses of morphine tested. DMR lesions produced a partial attentuation of the antinociceptive action of both the 3 and 10 mg doses. VR lesions produced a complete blockade of the 3 mg and only a partial attenuation of the 10 mg dose. In contrast, the combined (DMVR) lesions yielded virtually a total blockade of the 3 and 10 mg. Yet, as with the DMR and VR groups, the DMVR lesions failed to produce a significant antagonism on either of the nociceptive tests at the 30 mg dose. These findings suggest that the ascending and descending fiber systems emanating from the dorsal/median and ventral raphe, respectively, facilitate the expression of morphine-induced analgesia but that neither system alone can be regarded as essential for the manifestation of the antinociceptive effects of systematically administered morphine.     

The development of morphine antinociceptive tolerance in nitric oxide synthase-deficient mice

Elevations in nitric oxide (NO) have been implicated in the development of morphine antinociceptive tolerance. This study was conducted to establish the role of specific isoforms of NO synthase (NOS) in morphine tolerance development using genetically modified mice. METHODS: Three groups of mice (endothelial NOS [eNOS]-deficient, neuronal NOS [nNOS]-deficient, and NOS-competent) were used in this experiment. On Day 1, the analgesic response (radiant heat tail-flick) to a challenge dose of morphine (4 mg/kg) was determined over 3 hr. Tolerance was induced on Days 1-5 by administering morphine subcutaneously (10 mg/kg) or L-arginine, a NO precursor, intraperitoneally (200 mg/kg), twice daily. Analgesic response to the challenge dose was determined again on Day 6. RESULTS: Following sustained morphine administration, nNOS-deficient mice exhibited less tolerance development when compared to the control group, although measurable tolerance still occurred. Mice deficient in eNOS evidenced a degree of tolerance similar to that of control. Prolonged L-arginine administration produced significant functional tolerance to morphine in NOS-competent and eNOS-deficient mice. The loss of morphine responsivity after L-arginine administration was similar to that after morphine pretreatment. L-Arginine did not affect the antinociceptive response to morphine in mice deficient in nNOS, suggesting that the small degree of morphine-induced tolerance in this group occurs through an alternate pathway. CONCLUSIONS: These data demonstrate the pivotal role of the neuronal isoform of NOS in development of morphine antinociceptive tolerance. Furthermore, tolerance development appears to be predominantly a NO-mediated process, but likely is augmented by a secondary (non-NO) pathway.