Analgesic Effect Of Indomethacin Research Articles

Poly (ε-caprolactone) nanoparticles loaded with indomethacin and Nigella Sativa L. essential oil for the topical treatment of inflammation

Indomethacin has a high anti-inflammatory potential and an acceptable efficiency for external application. However, indomethacin can cause several side effects. It is crucial to reduce the employed indomethacin dosage and accordingly associated side effects. Therefore, topical delivery of indomethacin is as an interesting strategy. Thus, we designed poly (ε-caprolactone) based nanoparticles loaded with the Nigella Sativa L. Seeds Essential Oil (NSSEO) and indomethacin to enhance analgesic and anti-inflammatory effects of indomethacin. Nanoparticles were prepared by nanoprecipitation method. Prepared nanoparticles pre-stability study was also carried out. Nanoparticles size was ranged between 230 nm and 260 nm and zeta potential of nanoparticles was between – 20 mV and – 30 mV at pH around 6. Encapsulation efficiency of indomethacin and NSSEO within nanoparticles was respectively 70% and 84% while drug loading of indomethacin and NSSEO were 14% and 5.63% respectively. The size and zeta potential of nanoparticles was not changed significantly within 30 days of pre-stability investigation. Nanoparticles had a size in nano scale with round shape and a proper stability. Indomethacin and NSSEO were successfully encapsulated that would boost the anti-inflammatory and analgesic effects of indomethacin.

Crucial involvement of actin filaments in celecoxib and morphine analgesia in a model of inflammatory pain.

BackgroundCelecoxib exerted analgesic effects (hypoalgesia) reversed by opioid receptor antagonists in a model of inflammatory pain. To analyze this celecoxib-induced hypoalgesia further, we assessed the effects of several disruptors of cytoskeletal components in our model of inflammation.MethodsHyperalgesia to mechanical stimuli was induced in rat hind paws by intraplantar injection of carrageenan and measured using the Randall-Selitto method over the next 8 hours. The effects of systemic pretreatment with celecoxib and a range of cytoskeletal disruptors (colchicine, nocodazole, cytochalasin B, latrunculin B, acrylamide, each given by intraplantar injection) on carrageenan-induced hyperalgesia were similarly investigated. Morphine and other selective cyclo-oxygenase 1 (SC-560), cyclo-oxygenase 2 (SC-236), and nonselective cyclo-oxygenase (indomethacin) inhibitors were also tested under similar conditions.ResultsNone of the cytoskeletal disruptors affected the peak intensity of carrageenan-induced hyperalgesia, and its duration was increased only by nocodazole and colchicine. Pretreatment with celecoxib 30 minutes before carrageenan reversed the hyperalgesia and raised the nociceptive threshold (hypoalgesia). All analgesic effects of celecoxib were blocked by nocodazole, colchicine, cytochalasin B, and latrunculin B. Pretreatment with morphine also induced hypoalgesia in carrageenan-inflamed paws, an effect reversed by colchicine and cytochalasin B. However, the analgesic effects of indomethacin were not reversed by disruption of actin filaments with cytochalasin B or latrunculin B.ConclusionThese data strengthen the correlation between cytoskeletal structures and the processes of pain and analgesia.

Indirect role of β2-adrenergic receptors in the mechanism of analgesic action of nonsteroidal antiinflammatory drugs

Adrenal gland hormones have been shown to have a role in the antiinflammatory effect mechanism of nonsteroidal antiinflammatory drugs. This study investigates whether the analgesic effects of indomethacin, diclofenac sodium, aspirin, and nimesulide (IDAN; upper case letters of the four drugs we used) are also related to adrenal gland hormones. The analgesic effects of IDAN were studied in the carrageenan-induced inflammatory pain model using both intact and adrenalectomized rats. Paw withdrawal tests were performed in adrenalectomized rats that had been pretreated with phenoxybenzamine, propranolol, and metoprolol. This study was performed in Pharmacology and Biochemistry Laboratories of Faculty of Medicine. A total of 306 (114 intact and 192 adrenalectomized) male Albino Wistar rats were used. Adrernalectomy, drug administrations, pain model induction and pain threshold measurements were performed during the study. Although the analgesic effects of nonsteroidal antiinflammatory drugs were lost in adrenalectomized rats, they exerted significant analgesia in adrenalectomized rats that had been pretreated with prednisolone and adrenalin. All these drugs were found to decrease serum adrenalin concentration but did not change serum cortisole (corticosterone in rats) concentration. Prednisolone and adrenalin inhibited carrageenan-induced hyperalgesia in adrenalectomized rat groups pretreated with metoprolol or phenoxybenzamine, but not in rats given propranolol. Propranolol also negated the analgesic effects of IDAN in intact rats. The analgesic effects provided by either prednisolone or adrenalin could not be inhibited by the alpha1, alpha2, or beta1 blockers but disappeared when beta2 receptors were blocked. The analgesic effects of nonsteroidal antiinflammatory drugs appear to be related to endogenous adrenalin and cortisole. We have demonstrated that adrenalin and prednisolone play important roles in the analgesic effect mechanism of IDAN. Prednisolone and adrenalin produce analgesic effects through beta2-adrenergic receptors, suggesting an indirect role for beta2-adrenergic receptors in the analgesic effect mechanism of the nonsteroidal antiinflammatory drugs mentioned.

Evaluation of Chronopharmacodynamics of Indomethacin by the Kaolin-Induced Pain Model in Mice

We previously showed that the kaolin-induced writhe reaction exhibits 24h variation with a peak at the end of the resting period (14:00–18:00h) in mice maintained under light from 07:00 to 19:00h. In this study, we used this model to evaluate the administration-time-dependent (chronopharmacodynamic) effect of indomethacin. Indomethacin (0.5 mg/kg) was given orally to mice at 02:00, 08:00, 14:00, or 20:00h, and the suppressive effect on kaolin-induced writhing was determined after each timed dosing. After dosing at 08:00h, indomethacin remarkably reduced the number of writhes during the critical span of 14:00–18:00h—the time when writhing reaction was greatest during the 24h, while the suppressive effect of the medicine after dosing at the other clock times was relatively small. These data suggest the analgesic effect of indomethacin in mice with the kaolin-induced writhing is greater after dosing in the early resting period, which is similar to that reported in patients with nocturnal pain. The kaolin-induced pain mouse model seems to be useful for the chronopharmacodynamic evaluation of analgesic agents.

Relationship between pharmacokinetics and the analgesic effect of indomethacin in the rat.

The relationship between the pharmacokinetic properties and the analgesic effect of indomethacin (IDM) was evaluated on a carrageenin-induced inflammation model in the rat. Rats were administered the drug in one of two ways: intravenous (i.v.) IDM bolus or i.v. IDM infusion. The analgesic activity was measured by Randall-Selitto test. No correlation was observed between the analgesic effect and the plasma IDM concentration after i.v. bolus administration of IDM. However, in the case of infusion, IDM produced a dose-dependent analgesic effect. In this paper, we demonstrated that the plasma concentration of IDM maintained by i.v. infusion had a prolonged analgesic effect on the carrageenin-induced inflammation model.

Central mechanism of indomethacin analgesia

The analgesic effect of indomethacin was investigated by using the visceral pain model in rabbits. After intravenous administration of indomethacin (2 mg/kg), the maximum increase of the visceral pain threshold was 0.42 ± 0.31 mA (P < 0.05) . The analgesic effect lasted 40 min. After intraventricular microinjection of indomethacin (50 μg), the maximum increase of the visceral pain threshold was 0.37 ± 0.43 mA . After intravenous administration of indomethacin, the content of norepinephrine in perfusates of rabbit fourth ventricle was significantly increased from 18.10 ± 8.05 to 32.16 ± 6.15 mg/40 μ l (P < 0.05) , compared with data for the control group. The content of β-endorphin in the perfusate after indomethacin administration was decreased from 5–25 min and slightly increased from 25–35 min, compared with the data for the control group, but there was no significant difference (P > 0.05). Furthermore, intraventricular microinjection of phentolamine (50 μg) could block the analgesic effect of an intravenous injection of indomethacin, while naloxone could not. The results imply that prostaglandins of the central nervous system could induce hyperalgesia. Indomethacin injected centrally and peripherally has an analgesic effect on visceral pain. This analgesic effect is mediated by α-adrenoceptors. β-Endorphin does not participate in the analgesic action of indomethacin.

Analgesic and Anti-Ulcerogenic Effects of a Polar Extract from Leaves ofVernonia condensata

An aqueous crude extract and a polar fraction derived from this extract were prepared from leaves of Vernonia condensata Baker and assessed in standard rodent models of algesia and ulcerogenesis. Oral pretreatment with the lyophilized crude extract (200 mg/kg) significantly reduced mouse writhing counts caused by the i.p. injection of increasing concentrations (0.6-1.2%) of acetic acid (0.1 ml/10 g). In doses ranging from 50 to 400 mg/kg, the crude extract inhibited dose-dependently mouse writhing induced by acetic acid (0.6%) (ED50 = 241 mg/kg) and also markedly increased the sleeping time induced by thiopental. The polar fraction, prepared by washing out the crude extract with chloroform, did not alter sleeping time but kept the analgesic activity (ED50 = 154 mg/kg), indicating that these effects are indeed dissociated. In contrast, the tail flick response in the immersion test was not modified by the crude extract or the polar fraction. The relative potency with which polar fraction and non-steroidal anti-inflammatory drugs inhibited mouse writhing caused by acetic acid in mice was indomethacin >> dypirone > polar fraction > aspirin. Furthermore, the combined polar fraction/aspirin or polar fraction/indomethacin treatments presented a marked synergistic effect, in contrast to what was observed when submaximal doses of indomethacin and aspirin were coadministered, suggesting that polar fraction and aspirin like drugs may have complementary analgesic actions. Finally, despite being able to potentiate the analgesic effect of indomethacin in mouse writhing caused by acetic acid, the pretreatment with the polar fraction (200 mg/kg, oral) significantly prevented indomethacin-induced ulcers in rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Interaction of indomethacin and aspirin or mepirizole in rats as shown by gastrointestinal ulcerogenic and anti-inflammatory activities.

The interaction of indomethacin and aspirin or mepirizole was studied in rats. Concomitant oral administration of aspirin and indomethacin had no significant influence on the gastro-ulcerogenicity of indomethacin alone, but caused significantly less intestinal damage than an identical dose of indomethacin alone. In proportion to the inhibitory activity of intestinal lesions, aspirin also showed the activity that antagonized significantly the shortening of small intestinal length, loss of body weight and delay of charcoal transport in the intestine induced by indomethacin alone. Aspirin tended to reduce also the anti-inflammatory and analgesic effects of indomethacin in combined administration. On the other hand, mepirizole significantly reduced both gastric and intestinal ulcerogenicities by indomethacin alone in concomitant oral administration and inhibited dose-dependently the incidence and severity of those lesions. The inhibitory activity of gastrointestinal lesions by mepirizole was in proportion to the activities that antagonized the shortening of the small intestine, loss of body weight and delay of charcoal transport by indomethacin. Moreover, in contrast to aspirin, mepirizole exerted more potent anti-inflammatory and analgesic effects in combined administration than in the single administration of indomethacin. Therefore, aspirin reduced both the intestinal side effect and the anti-inflammatory effect induced by indomethacin in combination, while the combination of mepirizole reduced the gastrointestinal side effects by indomethacin alone, but seemed to be additive in the anti-inflammatory effect.