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.

The false-positive responses of analgesic drugs to the intradermal serotonin- and compound 48/80-induced scratches as an animal model of itch.

Intradermal injection of pruritogens such as serotonin, histamine and compound 48/80 into the skin and then, the evaluation of the scratching behavior is the commonly used animal model to advance pruritic research and drug development. However, predictive validity of this model is poorly documented. There is a close interaction between itch and pain sensations with regard to mediation through an anatomically and functionally identical neuronal pathway. One approach is whether the existing animal model of itch differentiates itch or pain to show efficacy of clinically effective analgesic drugs as a back translation. In this study, we explored the effects of different group of analgesic drugs on serotonin and compound 48/80-induced scratching behavior in Balb-C mice. Serotonin (25 µg) and compound 48/80 (100 µg) was injected intradermally in a volume of 50 µl into the rostral part of skin on the back of male mice and scratches were counted for a 30-min observation period. Morphine (1, 3, 10 mg/kg), tramadol (20, 40, 80 mg/kg), cannabinoid agonist CP 55,940 (0.1, 0.3, 1 mg/kg), paracetamol (100, 200, 300 mg/kg) and diclofenac (50, 100, 200 mg/kg) were given intraperitoneally 30 min prior to pruritogen injection. The analgesic drugs dose dependently blocked serotonin and compound 48/80-induced straching behavior with exerting complete inhibition at certain doses. Our data suggests that intradermal pruritogen-induced scratching models may not discriminate pain and itch sensations and give false positive results when standard analgesic drugs are used.

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.

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

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.

After myringotomy, can topical Mesna application be an alternative method to ventilation tube application?

Sodium-2-mercaptoethanesulfonate (Mesna) is a mucolytic substance that is also used for chemically assisted tissue dissection in otological surgery. We investigated the effects of Mesna as a chemical agent on the closing time of perforation of the eardrum in an experimental animal model. We performed simple myringotomy with a knife on 44 tympanic membranes of 22 rats. Four rats were excluded from the study because of serosity in their ears. Rats were divided into two study groups and a control group. These groups were the Mesna-administered group (Group A) (8 rats, 15 tympanic membranes), the saline-administered group (Group B) (8 rats, 14 tympanic membranes) and the control (native) group (6 rats, 11 tympanic membranes) (Group C). We applied Mesna locally for 20 min following myringotomy. Examination was made with an otoendoscope on days 1, 2, 3, 5, and 7, and patency rates were recorded. According to our results, we found that the closing time of the tympanic membrane was significantly longer in the Mesna group than in the saline administrated and native group. After myringotomy procedure, the application of a single dose of Mesna may contribute to the recovery duration of middle-ear pathologies by delaying the closing time of tympanic membrane perforation. However, Mesna cannot be an alternative method for the application of ventilation tubes.

Effects of paroxetine on cutaneous wound healing in healthy and diabetic rats.

OBJECTIVE: The aim of this study was to evaluate the histologic effects of acute paroxetine administration on wound healing in healthy and streptozotocin-induced diabetic rats. DESIGN: This study has a randomized controlled experimental design. SETTING: Healthy (n = 32) and diabetic (n = 32) rats were further divided into 2 groups of saline or paroxetine administration. PARTICIPANTS: Sixty-four male Sprague-Dawley rats were used in this study. INTERVENTIONS: Paroxetine was injected intraperitoneally every day. Full-thickness excision wounds were created with a 4-mm dermal punch on the back of all rats. The healing wound area was removed with a 6-mm dermal punch at postwounding days 1, 3, 7, and 14. MAIN OUTCOME MEASURES: Polymorphonuclear leukocyte, mononuclear inflammatory cell, fibroblast, and blood vessel counts and epithelialization were evaluated under light microscope. MAIN RESULTS: There was no statistically significant difference observed in the polymorphonuclear leukocyte, mononuclear inflammatory cell, and blood vessel counts in the healthy and diabetic rats with and without paroxetine administration. The number of fibroblasts was significantly higher at postwounding day 14 of the paroxetine-administered healthy rats compared with the saline-administered healthy rats (P = .04). However, the number of fibroblasts did not show any difference by paroxetine administration in the diabetic rats. There was no statistically significant difference in epithelialization regarding all the postwounding days, but complete epithelialization was observed in all rats on postwounding day 14 in the healthy and paroxetine-administered group. CONCLUSION: Short-term paroxetine administration may enhance cutaneous wound healing by increasing the number of fibroblasts and causing better epithelialization over time in healthy rats but not in diabetic rats.

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.

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.

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.

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 alpha(2)-adrenoceptor (alpha(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 microg/kg) and clonidine (10-80 microg/kg) produced a dose-dependent reduction in visceromotor response with 50% effective dose values of 10.5 and 37.6 microg/kg, respectively. Administration of the nonspecific alpha(2)-AR antagonist yohimbine (1 mg/kg), but not the peripherally restricted alpha(2)-AR antagonist MK-467 (1 mg/kg), abolished the antinociceptive effect of dexmedetomidine (10 microg/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 alpha(2)-ARs are not involved.

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.

Chronic treatment with fluoxetine and sertraline prevents forced swimming test-induced hypercontractility of rat detrusor muscle.

Serotonin (5-hydroxytryptamine, 5-HT) reuptake inhibitors represent important targets for the development of new treatments for detrusor overactivity and urinary incontinence. The present study was undertaken to investigate the effects of the forced swimming test (FST) on the contractile response of isolated rat detrusor muscle and to examine the effects of in vivo treatments of fluoxetine and sertraline on altered detrusor muscle contractility. Fluoxetine (20 mg/kg ip) and sertraline (10 mg/kg ip) were administered once a day for 14 days. Rats were exposed to the FST on the 15th day. After the test, detrusor muscles were removed and placed in organ baths, and the contraction responses induced by carbachol, potassium chloride (KCl) and electrical field stimulation (EFS) were recorded. The contractile responses of detrusor muscle strips to carbachol and electrical field stimulation were found to be increased at all carbachol doses and frequencies, respectively. FST also increased the contractile responses to KCl, which is used to test the differences in postreceptor-mediated contractions. The hypercontractile responses of detrusor strips to carbachol, EFS and KCl were abolished by treatment with both fluoxetine and sertraline. These treatments also decreased the immobility duration in the FST consistent with an antidepressant-like effect in this test. The results of this study provide the first evidence that FST increases contractility of the rat detrusor muscle, and this hypercontractility was abolished by chronic treatments of fluoxetine and sertraline at antidepressant doses by decreasing the postreceptor-mediated events.