Fatih Ilkaya

The antinociceptive effects of intravenous dexmedetomidine in colorectal distension-induced visceral pain in rats: the role of opioid receptors.

BACKGROUND: In comparison with cutaneous pain, the role of &agr;2-adrenoceptor (&agr;2-AR) agonists in visceral pain has not been extensively examined. We aimed to characterize the antinociceptive effect of IV dexmedetomidine on visceral pain in rats and to determine whether antinociception thus produced is mediated by opioid receptors. METHODS: Male Sprague Dawley rats (250–300 g) were instrumented with a venous catheter for drug administration and with enameled nichrome electrodes for electromyography of the external oblique muscles. Colorectal distension (CRD) was used as the noxious visceral stimulus, and the visceromotor response to CRD was quantified electromyographically before and 5, 15, 30, 60, 90, and 120 min after dexmedetomidine or clonidine administration. Antagonists were administered 10 min before dexmedetomidine. After confirmation of normal distribution of data, one-way analysis of variance with the Tukey-Kramer post hoc test was used for multiple comparison. RESULTS: IV administration of dexmedetomidine (2.5–20 &mgr;g/kg) and clonidine (10–80 &mgr;g/kg) produced a dose-dependent reduction in visceromotor response with 50% effective dose values of 10.5 and 37.6 &mgr;g/kg, respectively. Administration of the nonspecific &agr;2-AR antagonist yohimbine (1 mg/kg), but not the peripherally restricted &agr;2-AR antagonist MK-467 (1 mg/kg), abolished the antinociceptive effect of dexmedetomidine (10 &mgr;g/kg). In addition, inhibition of opioid receptors by naloxone (1 mg/kg) attenuated the antinociceptive effect of dexmedetomidine. CONCLUSION: Our data indicate that IV dexmedetomidine exerts pronounced antinociception against CRD-induced visceral pain and suggest that the antinociceptive effect of dexmedotimidine is mediated in part by opioid receptors, but peripheral &agr;2-ARs are not involved.

Effect of prenatal levetiracetam exposure on motor and cognitive functions of rat offspring

PURPOSE We aimed to establish the physical, motor, and cognitive teratogenic effect of levetiracetam exposure throughout pregnancy in rats. METHODS Thirty-two Sprague-Dawley pregnant female rats were divided into four groups. Groups 1-3 were treated with different doses of levetiracetam (25, 50, 100 mg/kg/d) from gestational days 1 to 18. Group 4 (control group) was treated with the same volume of saline. The day of occurrence for pinna detachment, incisor eruption, eye opening, ear opening, and fur development were also monitored. Righting reflex, negative geotaxis, and grip response were evaluated as measures of the development of reflexes. The cognitive and motor developments were established with T-maze, holeboard, Y-maze, locomotor activity, and passive avoidance test. RESULTS Levetiracetam exposure at 25, 50 and 100 mg/kg/d doses did not affect the timing of physical landmark developments. The dose of 100 mg/kg/d resulted in a significant delay in reaction time of the surface righting reflex compared to the control group. Two higher dose groups (50 and 100 mg/kg/d) had delay in the appearance of negative geotaxis reflex compared to the control group. Both groups maternally exposed to 50 and 100 mg/kg/d had a lower percentage of grip strength response comparing to control group on the first day of testing. On the second test day, only pups prenatally exposed to 100 mg/kg/d levetiracetam persistently had a significantly lower percentage of response. We could not find a significant difference between groups in tests for the locomotor activity, memory, and learning (T- and Y-maze, passive avoidance test), and explorative behavior (holeboard tests). CONCLUSION We showed that levetiracetam had only a transient impact on reflex maturation and no impact on physical and cognitive function in offspring of rats exposed to the drug during pregnancy. Levetiracetam may become a promising candidate for the treatment of epileptic women in pregnancy.

Antidepressant-like effects of echo-planar magnetic resonance imaging in mice determined using the forced swimming test

Echo-planar magnetic resonance imaging (EP-MRI), which is novel variant of MRI, is thought to have antidepressant properties in humans and animal models. Using the forced swimming test (FST), we investigated which monoaminergic system in mice is affected by EP-MRI. The short- and long-term effects of EP-MRI on immobility time in the FST and motor activity within a locomotor activity cage were examined. Two groups of mice underwent 20 min of EP-MRI in an MR scanner (Siemens, 1.5 T Symphony) either 23.5 or 1 h before the start of the second session of the FST. In both groups, the immobility duration in the FST was reduced, similar to effective antidepressant drug treatments. Climbing behavior in the 1-h group and swimming behavior in the 23.5-h group increased significantly, similar to that seen after the administration of desipramine (a noradrenaline reuptake inhibitor) and sertraline (a selective serotonin reuptake inhibitor), respectively. The findings support the hypothesis that EP-MRI has an antidepressant-like effect. We suggest that the antidepressant-like effect begins in the early period with noradrenaline systems and is maintained in the late period with serotonin systems.

The antinociceptive effects of intravenous tianeptine in colorectal distension-induced visceral pain in rats: The role of 5-HT3 Receptors.

Tianeptine is an unusual tricyclic antidepressant drug. In this study, we aimed to investigate the antinociceptive effect of tianeptine on visceral pain in rats and to determine whether possible antinociceptive effect of tianeptine is mediated by serotonergic (5-HT(2,3)) and noradrenergic (α(1,2)) receptor subtypes. Male Sprague Dawley rats (250-300 g) were supplied with a venous catheter, for drug administrations, and enameled nichrome electrodes, for electromyography, at external oblique musculature. Colorectal distension (CRD) was employed as the noxious visceral stimulus and the visceromotor response (VMR) to CRD was quantified electromyographically before and 5, 15, 30, 60, 90 and 120 min after tianeptine administration. Antagonists were administered 10 min before tianeptine for their ability to change tianeptine antinociception. Intravenous administration of tianeptine (2.5-20 mg/kg) produced a dose-dependent reduction in VMR. Administration of 5-HT(3) receptor antagonist ondansetron (0.5, 1 and 2 mg/kg), but not 5-HT(2) receptor antagonist ketanserine (0.5, 1 and 2 mg/kg), reduced the antinociceptive effect of tianeptine (10mg/kg). In addition, administration of α(1)-adrenoceptor antagonist prazosin (1 mg/kg) or α(2)-adrenoceptor antagonist yohimbine (1 mg/kg) did not cause any significant effect on the tianeptine-induced antinociception. Our data indicate that intravenous tianeptine exerts a pronounced antinociception against CRD-induced visceral pain in rats, and suggests that the antinociceptive effect of tianeptine appears to be mediated in part by 5-HT(3) receptors, but does not involve 5-HT(2) receptors or α-adrenoceptors.

The antinociceptive effect of intravenous imipramine in colorectal distension-induced visceral pain in rats: The role of serotonergic and noradrenergic receptors☆ , ☆☆

It has been shown that imipramine, a tricyclic antidepressant (TCA), is a potent analgesic agent. However, the effect of imipramine on visceral pain has not been extensively investigated. In the current study, our aim was to characterise the putative analgesic effect of intravenous imipramine on visceral pain in rats. Our second aim was to assess the involvement of serotonergic (5-HT₂,₃,₄) and noradrenergic (α(2A, 2B, 2C)) receptor subtypes in this putative antinociceptive effect of imipramine. Male Sprague Dawley rats (250-300 g) were implanted with venous catheters for drug administration and implanted with enamelled nichrome electrodes for electromyography of the external oblique muscles. Noxious visceral stimulation was applied via by colorectal distension (CRD). The visceromotor responses (VMRs) to CRD were quantified electromyographically before and after imipramine administration at 5, 15, 30, 60, 90 and 120 min. In the antagonist groups, the agents were administered 10 min before imipramine. The administration of imipramine (5-40 mg/kg) produced a dose-dependent reduction in VMR. The administration of yohimbine (a nonselective α₂-adrenoceptor antagonist, 1 mg/kg), BRL-44408 (an α(2A)-adrenoceptor antagonist, 1 mg/kg) or MK-912 (an α2C-adrenoceptor antagonist, 300 μg/kg) but not imiloxan (an α(2B)-adrenoceptor antagonist, 1 mg/kg) inhibited the antinociceptive effect of imipramine (20 mg/kg). Additionally, ketanserin (a 5-HT₂ receptor antagonist, 0.5, 1, and 2 mg/kg) and GR113808 (a 5-HT₄ receptor antagonist, 1 mg/kg) enhanced, and ondansetron (a 5-HT₃ receptor antagonist, 0.5, 1, and 2 mg/kg) failed to alter the imipramine-induced antinociceptive effect. Our data demonstrated that, in the CDR-induced rat visceral pain model, intravenous imipramine appeared to have antinociceptive potential and that α(2A)-/α(2C)-adrenoceptors and 5-HT₂/5-HT₄ receptors may be responsible for the antinociceptive effect of imipramine on visceral pain in rats.

Can empirical hypertonic saline or sodium bicarbonate treatment prevent the development of cardiotoxicity during serious amitriptyline poisoning? Experimental research.

Summary Objective The aim of this experimental study was to investigate whether hypertonic saline or sodium bicarbonate administration prevented the development of cardiotoxicity in rats that received toxic doses of amitriptyline. Method Thirty-six Sprague Dawley rats were used in the study. The animals were divided into six groups. Group 1 received toxic doses of i.p. amitriptyline. Groups 2 and 3 toxic doses of i.p. amitriptyline, plus i.v. sodium bicarbonate and i.v. hypertonic saline, respectively. Group 4 received only i.v. sodium bicarbonate, group 5 received only i.v. hypertonic saline, and group 6 was the control. Electrocardiography was recorded in all rats for a maximum of 60 minutes. Blood samples were obtained to measure the serum levels of sodium and ionised calcium. Results The survival time was shorter in group 1. In this group, the animals’ heart rates also decreased over time, and their QRS and QTc intervals were significantly prolonged. Groups 2 and 3 showed less severe changes in their ECGs and the rats survived for a longer period. The effects of sodium bicarbonate or hypertonic saline treatments on reducing the development of cardiotoxicity were similar. The serum sodium levels decreased in all the amitriptyline-applied groups. Reduction of serum sodium level was most pronounced in group 1. Conclusion Empirical treatment with sodium bicarbonate or hypertonic saline can reduce the development of cardiotoxicity during amitriptyline intoxication. As hypertonic saline has no adverse effects on drug elimination, it should be considered as an alternative to sodium bicarbonate therapy.

Opioid Receptors Contribute to Antinociceptive Effect of Tianeptine on Colorectal Distension-Induced Visceral Pain in Rats

Tianeptine is a clinically effective atypical antidepressant with distinct neurochemical properties. In this study, we aimed to investigate the contribution of opioid receptors in the antinociceptive effect of tianeptine on visceral pain in awake rats and to differentiate the subtype and the localization (central and/or peripheral) of these opioid receptors involved in this antinociception. Visceromotor response to noxious colorectal distension (CRD) was quantified with electromyographic recordings, obtained from previously implanted electrodes into the external oblique musculature of rats under anesthesia, before and after tianeptine administration. The opioid receptor antagonist naloxone hydrochloride (NLX) and peripherally restricted opioid receptor antagonist naloxone methiodide (NLXM) were administered intravenously 10 min before tianeptine (10 mg/kg, i.v.). The antinociceptive effect of tianeptine was abolished by NLX (1 and 2 mg/kg, i.v.), but was partially reduced by NLXM (1 and 2 mg/kg, i.v.). A µ-opioid receptor-selective dose (0.03 mg/kg, i.v.) of NLX, but not NLXM, significantly inhibited the antinociceptive effect of tianeptine. Our results suggest that antinociceptive effect of tianeptine on CRD-induced visceral nociception in rats involves the activation of both central and peripheral opioid receptors.

Effect of nonsteroidal anti-inflammatory drugs on colorectal distension-induced visceral pain

Objectives: To investigate nonsteroidal anti-inflammatory drugs effectiveness in colorectal distension (CRD)-induced visceral pain model. Materials and Methods: Male Sprague–Dawley (250–300 g) rats were anesthetized with ketamine (50 mg/kg, intraperitoneally [i.p.]) and chlorpromazine (25 mg/kg, i.p.). Two bipolar Teflon-coated Ni/Cr wire electrodes (80-M diameter) were placed in the abdominal external oblique muscle for the recording of electromyography. Jugular vein catheter was placed for the administration of drugs. CRD method was applied to evaluate of visceral pain. All drugs (paracetamol, meloxicam, metamizole, and dexketoprofen) administered intravenously. Results: Paracetamol 200, 400, and 600 mg/kg did not change the visceromotor response (VMR) when compare with the control group. Meloxicam 2 and 4 mg/kg showed no effect but at doses of 6 mg/kg meloxicam significantly ([51.9 ± 6.4%] [P < 0.001]) decreased VMR compared with the control group. Metamizole 200 mg/kg did not change responses but dose of 400 and 600 mg/kg metamizole reduced VMR. Dexketoprofen 2 and 4 mg/kg did not cause a change in VMR but 6 mg/kg dose significantly reduced response compared with the control group ([43.9 ± 3.9%, 36.8 ± 2.8%, 34.8 ± 2.5%, 42.1 ± 4.8%, 40.7 ± 3.5%, 36.4 ± 2.7%, and 26.1 ± 2.2%]; from 10 min to 70 min, respectively, [P < 0.05]). Conclusion: Metamizole, dexketoprofen and meloxicam show antinociceptive effect with different duration of action on CRD-induced visceral pain model. This condition can be explained due to different chemical structures and different mechanisms which play a role in modulation of pain.

The combination of agomelatine and ritanserin exerts a synergistic interaction in passive avoidance task

Agomelatine is a potent agonist at melatonergic 1 and 2 (MT1 and MT2) receptors and an antagonist at serotonin-2C (5HT-2C) receptors. It was suggested that psychotropic effects of agomelatine is associated with its melatonergic and serotonergic effects. In this study, we aimed to evaluate the effects of agomelatine alone or in combination with ritanserin (5HT-2A/2C antagonist) on memory and learning. Male Balb-C mice (25–30 g) were used, and all drugs and saline were administrated by intraperitoneal (i.p.) route 30 min prior to evaluating retention time. Whilst agomelatine was administered at the doses of 1, 10 and 30 mg/kg, ritanserin was administered at the doses of 0.1, 1 and 10 mg/kg. To evaluate memory function, passive avoidance test was used. On the first day, acquisition time and on the second day (after 24h), retention time of mice were recorded. To evaluate the synergistic activity, only the least doses of agomelatine and ritanserine were used, that is, 1 and 0.1 mg/kg, respectively. Scopolamine (1 mg/kg) was used as a reference drug, so it was combined with drug groups. Our results show that 5HT-2A/2C receptor antagonist ritanserin (1 and 4 mg/kg, i.p.) and agomelatine (10 and 30 mg/kg, i.p.) improve memory deficit induced by scopolamine, whilst a synergistic interaction is observed between ritanserin and agomelatine (0.1 mg/kg and 1 mg/kg, i.p., respectively) when they were administered at their ineffective doses. According to our findings, we concluded that agomelatine improves memory deficit and thus improves the effect of agomelatine arises from its 5HT-2C receptor antagonist activity.