Nedim Durmus

Effects of alpha 2-adrenoceptor agonists dexmedetomidine and guanfacine on morphine analgesia and tolerance in rats

Abstract Background. Alpha 2 (α2)-adrenoceptor agonists may be useful for their potential to increase or prolong opioid analgesia while attenuating the development of opioid tolerance. The purpose of this study was to investigate the effects of dexmedetomidine and guanfacine (α2-adrenoceptor agonists) on morphine analgesia and tolerance in rats. Methods. Adult male Wistar albino rats weighing 195–205 g were used. To constitute morphine tolerance, animals received morphine (50 mg/kg) once daily for 3 days. After the last dose of morphine had been injected on day 4, morphine tolerance was evaluated by analgesia tests. The analgesic effects of dexmedetomidine (20 μg/kg), guanfacine (0.5 mg/kg), MK-467 (0.25 mg/kg), and morphine were estimated at 30-min intervals (0, 30, 60, 90, and 120 min) by tail-flick and hot-plate analgesia tests. Results. Our findings indicate that dexmedetomidine and guanfacine attenuated the expression of morphine tolerance. In addition, administration of dexmedetomidine with morphine increased morphine analgesia. On the contrary, data suggested that MK-467 (an α2-adrenoceptor antagonist) decreased morphine analgesia and increased morphine tolerance in analgesia tests. Conclusion. In conclusion, we observed that co-injection of dexmedetomidine or guanfacine with morphine attenuated the expression of tolerance to the analgesic effect of morphine and that dexmedetomidine enhanced the morphine analgesia.

In Vitro Antimicrobial, Antioxidant, and Antispasmodic Activities and the Composition of the Essential Oil of Origanum acutidens (Hand.-Mazz.) Ietswaart

The radical scavenging, antimicrobial, and antispasmodic activities and the composition of Origanum acutidens (Hand.-Mazz.) Ietswaart (Order Labiatte) essential oil were evaluated in vitro. Gas chromatography/mass spectrometry analysis of the oil resulted in the identification of 20 compounds, representing 93.61% of the oil; carvacrol (65%) was the main component. The sample was also subjected to a screening for antioxidant activity by using the 1,1-diphenyl-2-picrylhydrazyl and beta-carotene/linoleic acid assays. The essential oil exhibited strong antioxidant activity. Using the agar disk diffusion method, antimicrobial activities of the essential oils were determined for nine microorganisms; antimicrobial activity was shown against eight of them. O. acutidens oil exhibited spontaneous contractions in rat ileum at the 100% level at 0.1 mg/mL level.

Effects of fluoxetine and LY 365265 on tolerance to the analgesic effect of morphine in rats

Morphine is widely used to treat chronic pain, however its utility is hindered by the development of tolerance to its analgesic effects. The aim of this study was to investigate effects of fluoxetine, a specific serotonin (5-HT) reuptake inhibitor, and LY 367265, an inhibitor of the 5-HT transporter and 5-HT2A receptor antagonist, on tolerance induced to the analgesic effect of morphine in rats. The study was carried out on male Wistar Albino rats (weighing 170-190 g). To constitute morphine tolerance, animals received morphine (50 mg/kg; s.c.) once daily for 3 days. After last dose of morphine, injected on day 4, morphine tolerance was evaluated. The analgesic effects of fluoxetine (10 mg/ kg; i.p.), LY 367265 (3 mg/kg; i.p.) and morphine were considered at 30-min intervals by tail-flick and hot-plate tests. The results showed that fluoxetine and LY 367265 significantly attenuated the development and expression of morphine tolerance. The maximal antinociceptive effects were obtained 30 min after administration of fluoxetine and 60 min after administration of LY 367265. In conclusion, we observed that co-injection of morphine with fluoxetine and LY 367265 increased the analgesic effects of morphine and delayed development of tolerance to morphine analgesia.

Chemical Composition, Antioxidant, Antimicrobial and Antispasmodic Activities of the Essential Oil of Juniperus excelsa subsp. excelsa

Abstract In this study, chemical composition, antioxidant, antimicrobial and antiospasmodic activities of the essential oil of the berries Juniperus excelsa Bieb. subsp. excelsa were evaluated in vitro. GC and GS-MS analysis of the oil resulted in the identification of 25 compounds, representing 97.2 % of the oil; α-pinene (46.1 %) was the main component. Essential oil showed remarkable antimicrobial activity against the test microorganisms. The sample was also subjected to a screening for its possible antioxidant activity by using 2,2-diphenyl-l- picrylhydrazyl (DPPH) and β-carotene-linoleic acid assays. It was exhibited moderate antioxidant activity in β-carotene-linoleic acid test system. In rat ileum, J. excelsa essential oil effect was directly investigated on spontaneous contractions. It has been found that amplitude and frequency did not change significantly at all dose concentrations. Amplitude has been inhibited % 25 and frequency has been inhibited % 20 at 1 mg/mL.

Investigation of the cardiac effects of pancuronium, rocuronium, vecuronium, and mivacurium on the isolated rat atrium.

BACKGROUND Pancuronium, vecuronium, rocuronium, and mivacurium are nondepolarizing neuromuscular blocking agents that affect the cardiovascular system with different potencies. Their cardiovascular effects are clinically significant in the anesthetic management of patients, particularly those undergoing cardiac surgery. OBJECTIVE We aimed to compare the cardiac effects of these compounds, such as heart rate and developed force, in one species under identical experimental conditions in isolated rat atria. METHODS The left or right atria of rats were removed and suspended in organ baths. Pancuronium, vecuronium, rocuronium, or mivacurium were added cumulatively (10(-9)-10(-5) M) in the presence and absence of the nonselective β-blocker propranolol (10(-8) M) and the noradrenaline reuptake inhibitor desipramine (10(-7) M), and heart rate changes were recorded in spontaneously beating right atria. Left atrial preparations were stimulated by electrical field stimulation using a bipolar platinum electrode, and the effects of cumulative concentrations of these nondepolarizing neuromuscular blocking agents on the developed force in the presence and absence of propranolol (10(-8) M) and desipramine (10(-7) M) were recorded. RESULTS Pancuronium increased heart rate in a dose-dependent manner compared with the control group (P < 0.027). Vecuronium, rocuronium, and mivacurium also increased heart rate in a dose-dependent manner, but the changes were not statistically significant. Although propranolol decreased the pancuronium heart rate effect (P < 0.05), it did not change the heart rate effects with vecuronium, rocuronium, or mivacurium. Desipramine did not change the heart rate effects of vecuronium, rocuronium, mivacurium, or pancuronium. All 4 drugs increased developed force in a dose-dependent manner; the increases were significant at 10(-5) M concentration for pancuronium and at 10(-6) and 10(-5) M concentrations for vecuronium, rocuronium, and mivacurium (P < 0.038). These increases in developed force were abolished with the addition of propranolol. Desipramine did not change the developed force effects of any of the 4 drugs. CONCLUSIONS The heart rate effect of pancuronium and developed force effects of pancuronium, vecuronium, rocuronium, and mivacurium may occur via direct stimulation of β receptors. Although our investigation was an in vitro study, the effects found may be important especially under pathologic conditions, such as hypertension, in which patients usually use β-blocking agents, which cause β receptor upregulation.

Evaluation of effects of T and N type calcium channel blockers on the electroencephalogram recordings in Wistar Albino Glaxo/Rij rats, an absence epilepsy model

Objectives: It is suggested that excessive calcium entry into neurons is the main triggering event in the initiation of epileptic discharges. We aimed to investigate the role of T and N type calcium channels in absence epilepsy experimental model. Materials and Methods: Wistar Albino Glaxo/Rij (WAG/Rij) rats (12–16 weeks old) were randomly allocated into four groups; sham, mibefradil (T type calcium channel blocker), w-Conotoxin MVIIA (N type calcium channel blocker), and mibefradil + w-Conotoxin MVIIA. Beta, alpha, theta, and delta wave ratios of EEG recordings and frequency and duration of spike wave discharges (SWDs) were analyzed and compared between groups. Results: Beta and delta recording ratios in 1 μM/5 μl mibefradil group was significantly different from basal and other dose-injected groups. Beta, alpha, and theta recordings in 0.2 μM/5 μl w-Conotoxin MVIIA group was significantly different from basal and other dose-injected groups. In w-Conotoxin MVIIA after mibefradil group, beta, alpha, and theta recording ratios were significantly different from basal and mibefradil group. Mibefradil and w-Conotoxin MVIIA significantly decreased the frequency and duration of SWDs. The decrease of frequency and duration of SWDs in mibefradil group was significantly different from w-Conotoxin MVIIA group. The frequency and duration of SWDs significantly decreased in w-Conotoxin MVIIA after mibefradil group compared with basal, mibefradil, and w-Conotoxin MVIIA groups. Conclusions: We concluded that both T and L type calcium channels play activator roles in SWDs and have positive effects on frequency and duration of these discharges. These results are related with their central effects more than peripheral effects.

Soluble guanylyl cyclase activators increase the expression of tolerance to morphine analgesic effect

OBJECTIVES It is aimed to investigate the effects of guanylyl cyclase activation and inhibition on acute morphine antinociception and the development of tolerance to its effect. BACKGROUND Nitric oxide-soluble guanylyl cyclase signal transduction cascade suggested to play an important role in the development of tolerance to antinociceptive effects of morphine. METHODS Nociception was evaluated by tail flick and hot plate tests in male Wistar rats. The analgesic effects of intraperitoneal protoporphyrin IX (PPIX; an activator of soluble guanylyl cyclase), 3-morpholinosydnonimine hydrochloride (SIN-1; NO donor and activator of guanylyl cyclase), S-Nitroso-N-acetylpenicillamine (SNAP; an activator of guanylyl cyclase), 3,3-Bis (amino ethyl)-1-hydroxy-2-oxo-1-triazene (NOC-18; NO donor activating guanylyl cyclase) and 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ; an inhibitor of guanylyl cyclase) alone or in combination with subcutaneous morphine injection were evaluated. Their effects on morphine tolerance development were evaluated by giving these agents 20 minutes prior to twice daily morphine injection during tolerance development for 5 days. On day 6, the expression of morphine tolerance was determined. RESULTS PPIX, SIN-1, SNAP and NOC-18 significantly increased expression of morphine tolerance while ODQ decreased. CONCLUSION These data suggested that sGC activators have a significant role in tolerance to the analgesic effect of morphine (Tab. 1, Fig. 4, Ref. 29).

Zimelidine attenuates the development of tolerance to morphine-induced antinociception

Objectives: The aim of this study was to investigate effect of zimelidine (a serotonin reuptake inhibitor) on morphine-induced tolerance in rats. Materials and Methods: Male Wistar albino rats weighing 160–180 g were used in these experiments (n=72). A 3-day cumulative dosing regimen was used for the induction of morphine tolerance. To constitute of morphine tolerance, animals received morphine twice daily for 3 days. After the last dose morphine was injected on the fourth day, morphine tolerance was evaluated. The analgesic effects of zimelidine (15 mg/kg; i.p.) and morphine (5 mg/kg) were considered at 30-min time intervals (0, 30, 60, 90 and 120 min) by tail-flick and hot-plate analgesiometer (n=6 in each experimental group). Results: The results showed that zimelidine significantly attenuated the development and expression of morphine tolerance. The maximal antinociceptive effect of zimelidine was obtained at the 60 minutes measurements in the zimelidine group and at the 30 minutes measurements in the morphine tolerant group by the tail-flick and hot-plate tests. Administration of zimelidine with morphine showed additive analgesic effect. Conclusion: In conclusion, our results show that zimelidine reduces the development of tolerance to morphine-induced antinociception in rats.

Nifedipine Enhances the Relaxant Effects of Cyclo-Oxygenase Inhibitors on the Bovine Ciliary Muscle

BACKGROUND/AIMS The inhibition of cyclo-oxygenase (COX) enzymes and the blockade of Ca (2+) channels play an important role in the regulation of smooth muscle relaxation. This study was designed to investigate the relaxant effects of celecoxib, DFU (5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulphonyl)phenyl-2(5H)-furanone), and indomethacin, cyclo-oxygenase (COX-1 and -2) inhibitors, in the absence or presence of a nifedipine, L-type Ca(2+) channel blocker, on bovine ciliary muscle. METHODS Ciliary muscle strips (n = 12) were mounted in organ baths and tested for changes in isometric tension in response to celecoxib, DFU, and indomethacin. The relaxant effects of celecoxib, DFU, and indomethacin on carbachol-induced contractions in the presence or absence of nifedipine were investigated. RESULTS Celecoxib (10(-7)-10(-4) M), DFU (10(-7)-10(-4) M), indomethacin (10(-7)-10(-4) M), and nifedipine (10(-7)-10(-4) M) inhibited the carbachol-induced contractions in a concentration-dependent manner. The E(max) value of indomethacin was significantly higher than the E(max) values of celecoxib and DFU in ciliary muscle (P < 0.05), with no significant change in pD(2) values (P > 0.05). The relaxation responses by celecoxib, DFU, and indomethacin were significantly increased in the presence of nifedipine (10(-6) M). There were no significant differences between pEC50 and values of celecoxib, DFU, and indomethacin in the absence of nifedipine (10(-6) M) (P > 0.05), but E(max)values were significantly increased (P < 0.05). CONCLUSIONS These results suggest that the celecoxib, DFU, and indomethacin cause relaxation in ciliary muscle precontracted with carbachol. Blockade of calcium channels with nifedipine in ciliary muscle may increase the relaxant effect of celecoxib, DFU, and indomethacin. The topical or systemic use of celecoxib, DFU, and indomethacin with nifedipine can cause blurred near vision due to ciliary muscle relaxation, and in ocular pain conditions caused by ciliary spasm, the pain can be decreased more easily by combined use of these drugs.

Effects of Cannabinoid Agonists on Sheep Sphincter of Oddi in vitro

Background/Aims: According to recent studies, the endocannabinoid system plays an important role in both physiological and pathophysiological situations. The purpose of the present study was to investigate the effects of cannabinoid (CB) agonists on isolated sheep sphincter of Oddi (SO)in vitro. Methods: The isolated sheep SO tissues were mounted in organ baths and tested for isometric tension and cyclic GMP levels (cGMP) in response to the non-selective CB receptor agonist WIN 55,212-2 and the potent CB1 receptor agonist methanandamide in the presence and absence of the selective CB1 antagonist SR 141716A, the selective CB2 antagonist SR 144528 and the nonspecific inhibitor of nitric oxide (NO) synthase L-NAME. Results: CB agonists relaxed SO in a concentration-dependent manner. These relaxations did not reduce in the presence of SR 144528 but were significantly reduced by SR 141716A and L-NAME. Carbachol significantly increased the cGMP levels compared with the control group and both of the CB receptor agonists significantly increased the cGMP levels compared with the control and carbachol groups. On the other hand, L-NAME prevented the increase in cGMP levels caused by CB agonists. Conclusion: These results show that the relaxation by the agonists may be through CB1 receptors. The decrease of CB relaxation responses by L-NAME, a nonspecific inhibitor of NO synthase, and the increase of cGMP levels in the SO tissues by CB agonists which decreased by L-NAME show that the relaxation effects of these agonists may also partially be via increasing the NO synthesis or release.