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Öğe 5-HT7 receptor activation attenuates thermal hyperalgesia in streptozocin-induced diabetic mice(Pergamon-Elsevier Science Ltd, 2012) Ulugol, Ahmet; Oltulu, Cagatay; Gunduz, Ozgur; Citak, Cihad; Carrara, Roberto; Shaqaqi, Mohammad Reza; Mansilla Sanchez, AliciaThe role of 5-HT7 receptors in the nociceptive processing received most attention during the last few years. The involvement of 5-HT7 receptors in nerve injury-induced neuropathic pain states have been reported only recently; however, there are no reports on its contribution in diabetic neuropathic pain. We therefore planned to investigate the effect of 5-HT7 receptor activation on the changes of nociceptive threshold in diabetic mice. Diabetes was induced by a single intraperitoneal injection of streptozocin (150 mg/kg, i.p.). The nociceptive responses in normal and diabetic animals were tested in the hot-plate and tail-flick assays. Both hot-plate and tail-flick latencies significantly shortened at 1-3/4 weeks (thermal hyperalgesia) and prolonged at 6-7 weeks (thermal hypoalgesia) after streptozocin administration. At the dose of 10 mg/kg, systemic injections of AS-19, a selective 5-HT7 receptor agonist, reduced thermal hyperalgesia at early stage of diabetes, but did not influence thermal hypoalgesia at late stage. Co-administration of SB-258719, a selective 5-HT7 receptor antagonist, at a dose that had no effect on its own (10 mg/kg), reversed the anti-hyperalgesic effect of AS-19. Our results indicate that systemic administration of 5-HT7 receptor agonists may have clinical utility in treating diabetic neuropathic pain. (C) 2012 Elsevier Inc. All rights reserved.Öğe Anti-allodynic and anti-hyperalgesic effects of ceftriaxone in streptozocin-induced diabetic rats(Elsevier Ireland Ltd, 2011) Gunduz, Ozgur; Oltulu, Cagatay; Buldum, Dilek; Guven, Rabia; Ulugol, AhmetGlutamate is the principal excitatory neurotransmitter in the central nervous system. Recent evidence suggests that beta lactam antibiotics offer neuroprotection by increasing glutamate transporter expression. Moreover, these antibiotics have been shown to prevent the development of tolerance and dependence to opioids, and reduce visceral and nerve injury-induced neuropathic nociceptive responses. The aim of this study is to observe the effect of a beta lactam antibiotic, ceftriaxone, on mechanical allodynia and mechanical hyperalgesia in diabetic rats. Diabetes was produced with the injection of a single dose of streptozocin (50 mg/kg, i.p.) and this procedure resulted in neuropathic pain behaviors in the hindpaws. Mechanical allodynia was detected with an electronic aesthesiometer, and mechanical hyperalgesia was studied using the method of Randall-Selitto. With its higher doses, ceftriaxone (100, 200 mg/kg, i.p.) reduced both mechanical allodynia and hyperalgesia. Dihydrokainic acid (10 mg/kg, i.p.), a selective GLT-1 transporter inhibitor, reversed the anti-allodynic and anti-hyperalgesic effects of ceftriaxone, at doses that produced no effect on its own. Our results indicate that ceftriaxone exerts an antinociceptive effect in streptozocin-induced diabetic rats and GLT-1 activation by beta lactam antibiotics may be a promising option in the treatment of diabetic neuropathy. (C) 2011 Elsevier Ireland Ltd. All rights reserved.Öğe Anti-Inflammatory and Antipruritic Effects of Remote Ischaemic Postconditioning in a Mouse Model of Experimental Allergic Contact Dermatitis(Mdpi, 2023) Gunduz, Ozgur; Sapmaz-Metin, Melike; Topuz, Ruhan Deniz; Kaya, Oktay; Karadag, Cetin Hakan; Ulugol, AhmetBackground and Objectives: Allergic contact dermatitis is a common type IV hypersensitivity reaction characterised by redness, itching, oedema and thickening of the skin. It occurs in about 7% of the population and its incidence is increasing. It has been observed that the preconditioning of tissues by exposing them to transient ischemia increases resistance to subsequent permanent ischemia, and this phenomenon is called ischemic preconditioning. It has been shown that conditioning in one organ can also protect other organs. The protective effect of remote ischemic preconditioning is thought to be based on the induction of anti-inflammatory responses. The aim of this project was to investigate the anti-inflammatory and antipruritic effects of remote ischemic postconditioning in a mouse model of experimental allergic contact dermatitis. Methods: Experimental allergic contact dermatitis was induced with 1-fluoro-2,4-dinitrobenzene. Remote ischemic postconditioning was performed at 3 and 25 h after the challenge. Ear thickness and number of scratches 24 and 48 h after challenge, as well as cytokine levels and the infiltration of mast cells, neutrophils, CD4(+) and CD8(+ )T lymphocytes in serum and ear tissue at 48 h were measured to determine the effect of RIPsC. Results: Remote ischemic postconditioning decreased ear thickness, one of the symptoms of allergic contact dermatitis (p < 0.0001). It had no significant effect on the number of scratches. It reduced serum IL-17 levels (p < 0.01). It alleviated local inflammation by suppressing CD8+ T lymphocyte and neutrophil infiltration. Conclusions: It was concluded that remote ischemic postconditioning may alleviate the symptoms of allergic contact dermatitis by suppressing CD8(+ )T lymphocyte and neutrophil infiltration and reducing IL-17 secretion.Öğe Attenuation of serotonin-induced itch responses by inhibition of endocannabinoid degradative enzymes, fatty acid amide hydrolase and monoacylglycerol lipase(Springer Wien, 2015) Tosun, Nurcan Calimli; Gunduz, Ozgur; Ulugol, AhmetItch and pain are two irritating sensations sharing a lot in common. Considering the antinociceptive effects of blockade of endocannabinoid degrading enzymes in pain states, we attempted to reduce scratching behavior by endocannabinoid modulation, i.e. by inhibiting fatty acid amide hydrolase (FAAH), monoacylglycerol lipase (MAGL), or cellular uptake of endocannabinoids. Scratching behavior was induced by intradermal injection of serotonin to Balb/c mice. URB597 (10 mg/kg, i.p.), a FAAH inhibitor, JZL184 (16 mg/kg, i.p.), a MAGL inhibitor, and AM404 (10 mg/kg, i.p.), an endocannabinoid transport inhibitor, were given to evaluate the effects of endocannabinoid modulation on scratching responses. Then, the CB1 receptor antagonist, AM251 (1 mg/kg, i.p.), and the CB2 receptor antagonist, SR144528 (1 mg/kg, i.p.), were administered to determine whether cannabinoid receptors mediate these effects. URB597 and JZL184, but not AM404, attenuated serotonin-induced scratches. The inhibitory effect of URB597 was reversed by SR144528, but cannabinoid receptor antagonists had no other effects on modulation by the inhibitors. We propose that augmenting the endocannabinoid tonus by inhibition of degradative enzymes, FAAH and MAGL, but not cellular uptake, may be a novel target for the development of antipruritic agents.Öğe Blockade of cannabinoid CB1 and CB2 receptors does not prevent the antipruritic effect of systemic paracetamol(Springer Heidelberg, 2014) Saglam, Gulis; Gunduz, Ozgur; Ulugol, AhmetCannabinoid CB1 receptors have been shown to mediate the antinociceptive, but not the hypothermic, action of the worldwide used analgesic, paracetamol. Since itch and pain sensations share many similarities, the purpose of the present study was to investigate whether blockade of cannabinoid CB1 and CB2 receptors participates in the antipruritic activity of paracetamol in mice. Scratching behavior was induced by intradermal serotonin injection into the rostral part of the back of the mice. After serotonin administration, scratching of the injected site by the hind paws were videotaped and counted for 30 min. Serotonin-induced scratching behavior was attenuated with high-dose paracetamol (300 mg/kg). The CB1 receptor antagonist, AM-251 (1 mg/kg), and the CB2 receptor antagonist, SR-144528 (1 mg/kg), did not alter the anti-scratching behavioral effect of paracetamol. Our results indicate that, in contrast to its antinociceptive action, but similar to its hypothermic effect, cannabinoid receptors are not involved in the antipruritic activity of paracetamol.Öğe Changes in nociceptin/orphanin FQ levels in rat brain regions after acute and chronic cannabinoid treatment in conjunction with the development of antinociceptive tolerance(Wiley-Blackwell, 2016) Ulugol, Ahmet; Topuz, Ruhan D.; Gunduz, Ozgur; Kizilay, Gulnur; Karadag, Hakan C.It has been indicated that acute and chronic morphine administrations enhance nociceptin/orphanin FQ (N/OFQ) levels in the brain, which might play role in the development of tolerance to the antinociceptive effect of morphine. Accordingly, N/OFQ receptor (NOP) antagonists have been shown to prevent the development of antinociceptive tolerance to morphine. Our aim is to observe whether cannabinoids, similarly to opioids, enhance N/OFQ levels in pain-related brain regions and whether antagonism of NOP receptors attenuates the development of tolerance to the antinociceptive effect of cannabinoids. Hot plate and Tail flick tests are used to assess the antinociceptive response in Sprague-Dawley rats. N/OFQ levels are measured in cortex, amygdala, hypothalamus, periaqueductal gray, nucleus raphe magnus and locus coeruleus of rat brains using Western blotting and immunohistochemistry. Within 9 days, animals became completely tolerant to the antinociceptive effect of the cannabinoid agonist WIN 55,212-2 (2, 4, 6 mg/kg, i.p.). Chronic administration of JTC-801, a NOP receptor antagonist, at a dose that exerted no effect on its own (1 mg/kg, i.p.), attenuated development of tolerance to the antinociceptive effect of WIN 55,212-2 (4 mg/kg, i.p.). Western blotting and immunohistochemistry results showed that N/OFQ levels significantly increased in amygdala, periaqueductal gray, nucleus raphe magnus and locus coeruleus of rat brains when WIN 55,212-2 was combined with JTC-801. We hypothesize that, similar to opioids, chronic cannabinoid + NOP antagonist administration may enhance N/OFQ levels and NOP receptor antagonism prevents development of tolerance to cannabinoid antinociception.Öğe Contribution of nociceptin/orphanin FQ receptors to the anti-nociceptive and hypothermic effects of dipyrone(Cambridge Univ Press, 2015) Ertin, Ismet Hande; Gunduz, Ozgur; Ulugol, AhmetBackground Dipyrone is one of the most commonly used non-opioid analgesic and antipyretic drug. Its anti-nociceptive and hypothermic effects have long been suspected to be centrally mediated. The involvement of the most recently discovered opioid peptide, nociceptin/orphanin FQ (N/OFQ), and its receptor (NOP) in pain transmission is controversial. It appears to be pro-nociceptive when administered supra-spinally, but exerts anti-nociceptive effects when injected spinally or systemically. Objective Investigation of the role of the N/OFQ system in paracetamol-induced anti-nociception and hypothermia led us to determine its role in the anti-nociceptive and hypothermic effects of dipyrone. Material and Methods Hot-plate and tail-flick tests were used to assess nociception, and a rectal thermometer was used to measure rectal temperature in mice. Results Mice injected with dipyrone (150, 300, 600 mg/kg, i.p.) displayed dose-related anti-nociception and hypothermia. The NOP receptor antagonist JTC-801 (3 mg/kg, i.p.), at a dose that exerted no effect when used alone, alleviated dipyrone-induced anti-nociception but did not reverse dipyrone-induced hypothermia. Conclusion We conclude that NOP receptors participate in the anti-nociceptive, but not in the hypothermic, effects of dipyrone.Öğe Contribution of spinal 5-HT5A receptors to the antinociceptive effects of systemically administered cannabinoid agonist WIN 55,212-2 and morphine(Canadian Science Publishing, Nrc Research Press, 2018) Aksu, Ahmet Goktan; Gunduz, Ozgur; Ulugol, AhmetThe antinociceptive effects of cannabinoids and opioids have been known for centuries. Serotonin and its receptors are also known to play important roles in nociception. However, the contribution of spinal 5-HT5A receptors in antinociceptive effects of cannabinoids and opioids has not been studied. We conducted this study to clarify spinal mechanisms of the actions of the antinociceptive effects of cannabinoids and opioids. Hot plate and tail fl(i)ck tests were used to assess the antinociceptive activity in Balb/c mice. WIN 55,212-2, a nonselective CB1 and CB2 agonist, and morphine exerted significant antinociceptive effects at 1, 3, and 10 mg/kg doses administered intraperitoneally in both hot plate and tail flick tests. The selective 5-HT5A receptor antagonist SB-699551 (10 nmol/mouse) was administered intrathecally 10 min before the agonists. SB-699551 significantly reduced the antinociceptive effect of both WIN 55,212-2 and morphine. In the rotarod test, WIN 55,212-2 disrupted the motor coordination at a dose of 10 mg/kg, while morphine did not affect this function at any dose. Our findings show that spinal 5-HT5A receptors are involved in the antinociceptive effects of WIN 55,212-2 and morphine.Öğe Descending serotonergic and noradrenergic systems do not regulate the antipruritic effects of cannabinoids(Cambridge Univ Press, 2016) Todurga, Zeynep Gizem; Gunduz, Ozgur; Karadag, Cetin Hakan; Ulugol, AhmetBackground: For centuries, cannabinoids have been known to be effective in pain states. Itch and pain are two sensations sharing a lot in common. Objective: The goal of this research was to observe whether the cannabinoid agonist WIN 55,212-2 reduces serotonin-induced scratching behaviour and whether neurotoxic destruction of descending serotonergic and noradrenergic pathways mediate the antipruritic effect of WIN 55,212-2. Material and methods: Scratching behaviour was induced by intradermal injection of serotonin (50 mu g/50 mu l/mouse) to Balb/c mice. The neurotoxins 5,7-dihydroxytryptamine (5,7-DHT, 50 mu g/mouse) and 6-hydroxydopamine (6-OHDA, 20 mu g/mouse) are applied intrathecally to deplete serotonin and noradrenaline in the spinal cord. WIN 55,212-2 (1, 3, 10 mg/kg, i.p.) dose-dependently attenuated serotonin-induced scratches. Neurotoxic destruction of neither the serotonergic nor the noradrenergic systems by 5,7-DHT and 6-OHDA, respectively, had any effect on the antipruritic action of WIN 55,212-2. Conclusion: Our findings indicate that cannabinoids dose-dependently reduce serotonin-induced scratching behaviour and neurotoxic destruction of descending inhibitory pathways does not mediate this antipruritic effect.Öğe Does dipyrone produce anxiolytic-like effects in mice?(Cukurova Univ, Fac Medicine, 2019) Topuz, Ruhan Deniz; Gunduz, Ozgur; Dokmeci, Dikmen; Karadag, Cetin Hakan; Ulugol, AhmetPurpose: Paracetamol has been shown to exert anxiolytic-like effects mediated by endocannabinoids via cannabinoid CB1 receptors. Dipyrone is an analgesic with similar effects to paracetamol rather than non-steroidal anti-inflammatory drugs. Involvement of central structures to its effects are long under debate, whereas recent findings suggesting contribution of cannabinoid CB1 receptors to its antinociceptive effect support this argument. Taken together, the purpose of this study was to investigate whether dipyrone possesses anxiolytic-like behavior; contribution of cannabinoid CB1 and CB2 receptors and TRPV1 receptors will be determined in case of observing any effect of dipyrone in anxiety tests. Material and Methods: Balb-c mice effects of dipyrone (150, 300, 600 mg/kg, i.p) were assessed in three-chamber social interaction, open-field, elevated plus-maze and rota rod tests. The cannabinoid CB1 antagonist AM251 (1 mg/kg i.p.), the CB2 antagonist SR 144528 (1 mg/kg i.p.) and the TRPV1 antagonist capsazepine (3 mg/kg i.p) were going to be administered before dipyrone injections if any effect of dipyrone occurs. Results: Dipyrone had no effect at any dose in behavioral tests (three-chamber social interaction, open-field, elevated plus-maze and rota rod tests). Therefore, dipyrone is not tested together with the cannabinoid CB1 and CB2 antagonists and the TRPV1 receptor antagonist. Conclusion: Unlike paracetamol, dipyrone did not possess anxiolytic-like effects in mice. Discrepancies in experimental models and methodologies may be the reason of our results.Öğe The Effect of Nitric Oxide Synthase Inhibitors on the Development of Analgesic Tolerance to Dipyrone in Mice(Taylor & Francis Ltd, 2009) Yilmaz, Ibrahim; Ulugol, AhmetRecent investigations have shown that, similarly to opioids, tolerance develops to the analgesic effects of nonsteroidal anti-inflammatory drugs (NSAIDs). Nitric oxide has been shown to play an important role in opioid-induced analgesic tolerance; we, therefore, planned to determine if nitric oxide also plays role in the analgesic tolerance to dipyrone, a NSAID. Using the hot-plate test in mice, an analgesic tolerance developed to dipyrone with its 150 and 300 mg/kg intraperitoneal doses after 7 days; no tolerance was observed with its dose of 600 mg/kg. Neither 7-nitroindazole (50 mg/kg, i.p.), a neuronal NOS inhibitor, nor aminoguanidine (30 mg/kg, i.p.), an inducible NOS inhibitor, had any effect on dipyrone-induced analgesic tolerance with doses, which also had no analgesic effect when used alone. Our results show that nitric oxide does not play role in the analgesic tolerance to dipyrone; however, further experiments are required to delineate the mechanisms and to take preventive measures against this problem, which will possibly limit the use of NSAIDs.Öğe Endocannabinoid and N-acylethanolamide levels in rat brain and spinal cord following systemic dipyrone and paracetamol administration(Canadian Science Publishing, 2019) Topuz, Ruhan Deniz; Gunduz, Ozgur; Karadag, Cetin Hakan; Dokmeci, Dikmen; Ulugol, AhmetThe cannabinoid system has been suspected to play a role in the mechanisms of action of dipyrone and paracetamol. Our purpose was to measure the local endocannabinoid and N-acylethanolamide levels in the brain and spinal cord of rats following dipyrone and paracetamol administration. Nociception was assessed 1, 5, and 12 h following drug injections in Wistar rats, using tail-flick and hot-plate tests. The antinociceptive effects of dipyrone (150, 300, and 600 mg/kg, i.p.) and paracetamol (30, 100, and 300 mg/kg, i.p.) were observed. After administration of the highest doses of dipyrone and paracetamol, endocannabinoid (N-arachidonoylethanolamide (AEA), 2-arachidonoylglycerol (2-AG)) and N-acylethanolamide (palmitoylethanolamide (PEA), oleoylethanolamide (OEA)) levels were measured in the periaqueductal gray (PAG), rostral ventromedial medulla (RVM), and spinal cords of rats using tandem mass spectrometry with liquid chromatography. Increased 2-AG levels were observed in the PAG and the RVM 12 h after paracetamol injection; dipyrone exerted no action on 2-AG levels. Analgesic administrations led to a reduction in AEA levels in the RVM and spinal cord; similar decreases in PEA and OEA levels were observed in the RVM and the spinal cord. Dipyrone and paracetamol administrations appear to exert complicated effects on endocannabinoid and N-acylethanolamide levels in rats.Öğe The false-positive responses of analgesic drugs to the intradermal serotonin- and compound 48/80-induced scratches as an animal model of itch(Nencki Inst Experimental Biology, 2016) Ilkaya, Fatih; Yesilyurt, Ozgur; Seyrek, Melik; Gunduz, Ozgur; Ide, Tayfun; Akar, Ahmet; Ulugol, AhmetIntradermal 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 mu g) and compound 48/80 (100 mu g) was injected intradermally in a volume of 50 mu l into the rostra! 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.Öğe Involvement of cannabinoid CB1 receptors in the antinociceptive effect of dipyrone(Springer Wien, 2013) Elmas, Pinar; Ulugol, AhmetCannabinoid CB1 receptors have been implicated in the antinociceptive effect of paracetamol. In the current study, we examined whether blockade of CB1 receptors prevent the analgesic activity of dipyrone, in a similar way to paracetamol. Hot-plate and tail-flick tests were used to assess the antinociceptive activity in mice. Dipyrone and WIN 55,212-2, a cannabinoid agonist, exerted significant antinociceptive effects in both hot-plate and tail flick tests. The CB1 receptor antagonist, AM-251 (3 mg/kg), at a dose which had no effect when used alone, did not alter the antinociceptive effect of dipyrone, whereas completely prevented the antinociceptive activity of WIN 55,212-2 in both thermal antinociceptive tests. Our findings suggest that, unlike paracetamol, cannabinoid CB1 receptors do not participate in the antinociceptive action of dipyrone when acute pain tests used.Öğe Involvement of descending serotonergic and noradrenergic pathways in CB1 receptor-mediated antinociception(Pergamon-Elsevier Science Ltd, 2012) Dogrul, Ahmet; Seyrek, Melik; Yalcin, Bulent; Ulugol, AhmetCannabinoids produce antinociceptive and antihyperalgesic effects mainly through activation of the inhibitory CB1 receptors. The demonstration that antinociceptive effects of systemic cannabinoids are significantly diminished following surgical dorsolateral funiculus lesion provides evidence that supraspinal sites and descending pain modulatory pathways play crucial roles in systemic cannabinoid analgesia. In this review, we will firstly provide a background, brief overview of descending modulatory pathways followed by descending pathways implicated in cannabinoid analgesia. We will then describe the recent evidence of the involvement of descending serotonergic and noradrenergic pathways in CB1 receptor-mediated antinociception. This review will provide evidences that systemically administered cannabinoids reinforce the descending serotonergic and noradrenergic pathways to produce acute antinociceptive effects via spinal 5-HT7, 5-HT2A and alpha-2 adrenoceptors activation. (C) 2012 Elsevier Inc. All rights reserved.Öğe Lack of correlation between plasma asymmetric dimethylarginine (ADMA) levels and pain-related behaviors in neuropathic rats(Universitatsverlag Ulm Gmbh, 2011) Hafizoglu, Emin; Ulugol, AhmetObjectives: Recent research has demonstrated elevations of ADMA levels in many cardiovascular and metabolic diseases, and ADMA has also been proposed as a modulator of nociception in opiate tolerance and addiction. The present study was conducted to determine whether increased level of peripheral ADMA is implicated in tactile allodynia in rats with partial tight ligation of the sciatic nerve. Methods: Beginning from the 1st measurement after the ligation, paw withdrawal thresholds significantly reduced compared with duration-matched control animals, indicating that mechanical allodynia developed in sciatic nerve-ligated rats. Results: In both neuropathic and control groups, plasma levels of ADMA, SDMA, L-homoarginine and L-arginine remained unchanged throughout the experiment, and there were no significant differences between two groups in different durations. Conclusion: These results suggest that endogenous plasma ADMA, SDMA, L-homoarginine and L-arginine levels do not change during the different stages of neuropathic duration, and accordingly may not be implicated in tactile allodynia in neuropathic rats. (C) 2011 Elsevier GmbH. All rights reserved.Öğe Lack of effect of ceftriaxone, a GLT-1 transporter activator, on spatial memory in mice(Pergamon-Elsevier Science Ltd, 2013) Karaman, Ipek; Kizilay-Ozfidan, Gulnur; Karadag, C. Hakan; Ulugol, AhmetIn the central nervous system, glutamate appears to be the principal excitatory amino acid neurotransmitter. Recent findings show that beta-lactam antibiotics, by stimulating glutamate transporter (GLT-1) expression, offer neuroprotection. The purpose of our study is to observe the effect of ceftriaxone, a beta-lactam antibiotic, on spatial memory in mice. Male Balb-c mice, weighing 20-25 g, were trained in Morris water maze (n = 12 for each group) task. Animals were given 4 trials per day for 7 consecutive days to locate a hidden platform (acquisition phase). On the eighth day, the platform is removed and the animals were swum for one session of 60 s (retention phase). Learning and memory functions of the animals were evaluated based on-their performances in these tests. Ceftriaxone was given for 9 days at different doses (50, 100, and 200 mg/kg, i.p.); additionally, its acute effect was evaluated in one group (200 mg/kg, i.p.). Our immunohistochemistry findings indicate that ceftriaxone increases GLT-1 expression in CA1, CA3 and DG regions of hippocampus, especially with the dose of 200 mg/kg. Evaluation of the acquisition parameters, such as time to reach platform, distance moved, and mean distance to platform indicates that chronic ceftriaxone has no effect on learning curves of the animals. When retention phase parameters (e.g. time to reach target quadrant swim duration in target quadrant, and mean distance to platform area) are evaluated, it was found that both chronic and acute ceftriaxone did not affect memory at any dose used. In contrast to the contribution of GLT-1 expression to various central nervous system diseases, such as chronic pain, amyotrophic lateral sclerosis, Parkinson's disease and seizures, our findings suggest that ceftriaxone has no effect on spatial memory function in mice. (C) 2013 Elsevier Inc. All rights reserved.Öğe Modulatory role of asymmetric dimethylarginine (ADMA) in cannabinoid tolerance and dependence(Churchill Livingstone, 2009) Ulugol, AhmetNumerous studies have shown that opioids and cannabinoids share some pharmacological properties. Accordingly, similarly to opioids, tolerance and dependence develops after chronic use of cannabinoids. Nitric oxide (NO) has been shown to play important roles both in opioid- and cannabinoid-induced tolerance and dependence. The endogenous nitric oxide synthase (NOS) inhibitor, ADMA, levels have been shown to elevate, and L-arginine/ADMA ratio has been shown to reduce in many cardiovascular/metabolic disorders. Recently, ADMA has also been proposed as a modulator of nociception in opiate tolerance and dependence. Taken together, we hypothesized that ADMA and/or L-arginine/ADMA ratio may play a modulatory role in tolerance and dependence to cannabinoids. (C) 2009 Elsevier Ltd. All rights reserved.Öğe Modulatory role of the endogenous nitric oxide synthase inhibitor, asymmetric dimethylarginine (ADMA), in morphine tolerance and dependence in mice(Springer Wien, 2010) Gunduz, Ozgur; Karadag, Cetin Hakan; Ulugol, AhmetElevated plasma asymmetric dimethylarginine (ADMA) levels have been implicated in many cardiovascular and metabolic disorders. In the current work, we investigated the hypothesis that peripheral ADMA is an important contributor to opioid tolerance and dependence, by determining plasma ADMA levels during the development of tolerance and dependence to morphine in mice. Tolerance to and dependence on morphine were induced by repeated injections of morphine (10 mg/kg, s.c.) twice daily to male mice, divided into groups of 3-, 6-, 9- and 10-day injection duration. The loss of antinociceptive effect of morphine in the tail flick test was used for evaluating the degree of tolerance. Physical dependence was assessed following the administration of a 5 mg/kg dose of naloxone, by counting the occurrence of withdrawal jumps and forepaw tremors for 20 min. At the end of each period, animals were anesthetized and blood samples were collected from carotid artery. The plasma levels of ADMA, symmetric dimethylarginine (SDMA), l-homoarginine and l-arginine in morphine-tolerant and -dependent mice were not different from duration-matched control mice. Similarly, no difference was observed in plasma ADMA and the other molecules concentrations between groups of mice with different stages of development of tolerance and dependence. Our results suggest that endogenous plasma ADMA, SDMA, l-homoarginine and l-arginine levels remain unchanged during the development of morphine tolerance and dependence, and are not associated with these phenomena.Öğe Pharmacological and behavioral characterization of the saphenous chronic constriction injury model of neuropathic pain in rats(Springer, 2011) Gunduz, Ozgur; Oltulu, Cagatay; Guven, Rabia; Buldum, Dilek; Ulugol, AhmetThe aim of the present study was to develop a new experimental pain model by adapting the chronic constriction injury (CCI) model of the sciatic nerve to the exclusively sensory saphenous nerve in rats. Animals were divided into na < ve, sham, and two experimental groups, in which two or four 4-0 chromic gut ligatures were loosely ligated around the saphenous nerve. Then, behavioral signs of neuropathic pain were observed for 8 weeks. In rats with four ligatures, prominent mechanical allodynia and thermal hyperalgesia developed; these behavioral signs were not prominent in rats with two ligatures. Pharmacological analysis was made in rats with four loose ligations; morphine and WIN 55,212-2, a cannabinoid agonist, reversed all of the modalities tested, whereas gabapentin only suppressed mechanical allodynia and amitriptyline only reduced mechanical hyperalgesia. Our data establish a rat model of saphenous CCI with significant allodynia and hyperalgesia, which is sensitive to a number of analgesic compounds.
