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    Analysis of the anti-allodynic effects of combination of a synthetic cannabinoid and a selective noradrenaline re-uptake inhibitor in nerve injury-induced neuropathic mice
    (Wiley-Blackwell, 2016) Gunduz, O.; Topuz, R. D.; Karadag, C. H.; Ulugol, A.
    BackgroundCombining drugs not only reduces specific adverse effects of each of the drug at a higher dose but also may lead to enhanced efficacy. Tapentadol is a recently discovered analgesic possessing -opioid receptor agonism and noradrenaline re-uptake inhibition in a single molecule. Taking into consideration, the pharmacological similarities between opioids and cannabinoids, we assumed that combination of cannabinoids with noradrenaline re-uptake inhibitors might also be effective. We therefore aimed to determine whether combining 1:1, 1:3 and 3:1 fixed ratios of the synthetic cannabinoid WIN 55,212-2 and the selective noradrenaline re-uptake inhibitor maprotiline exert anti-allodynic synergy on nerve-injured neuropathic mice. MethodsPartial tight ligation of the sciatic nerve was made in mice; on pre-operative and post-operative 15 days basal mechanical allodynia, cold allodynia and motor function were assessed using von Frey filaments, hot/cold plate and rota rod apparatus. ResultsMechanical and cold allodynia developed in all groups on post-operative 15 days. Development of cold allodynia was statistically significant in all groups (p<0.05); therefore, cold allodynia was used in combination studies. As shown by isobolographic analysis, interactions of 1:1 and 3:1 ratios of WIN 55,212-2:maprotiline combinations were supra-additive, whereas 1:3 ratio was sub-additive. ConclusionsOverall, our data suggest that combination of a cannabinoid with a selective noradrenaline re-uptake inhibitor may offer a beneficial treatment option for neuropathic pain.
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    Effect of Activation of the GLT-1 Transporter by a Beta-Lactam Antibiotic on Serotonin-Induced Scratching Behavior in Mice
    (Springer, 2015) Gunduz, O.; Topuz, R. D.; Todurga, Z. G.; Duvan, K.; Karadag, C. H.; Ulugol, A.
    Glutamate is believed to be the predominant excitatory neurotransmitter in the networks responsible for itch-related behavior. Beta-lactam antibiotics were shown to exert neuroprotective effects by increasing expression of the glutamate transporter GLT-1. We observed whether repeated administration of the beta-lactam antibiotic ceftriaxone suppresses serotonin-induced itch-related behavior (similarly to the effect of this agent on pain transmission) in mice. Chronic, but not acute, ceftriaxone introductions reduced the number of serotonin-induced scratches; dihydrokainic acid, a selective GLT-1 transporter inhibitor, partly but significantly abolished this effect of ceftriaxone. Our findings suggest that GLT-1 activation by beta-lactam antibiotics looks promising for the treatment of chronic itch.
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    Effects of a Nociceptin Receptor Antagonist on Experimentally Induced Scratching Behavior in Mice
    (Springer, 2017) Aydemir, K. Duvan; Gunduz, O.; Ulugol, A.
    Itch and pain are two distressing sensations sharing a lot in common. In addition to the periphery, the central nervous system is proposed as a therapeutic target for the development of antipruritic drugs. The contribution of the most recently discovered opioid peptide, nociceptin/orphanin FQ (N/OFQ) and its receptor (NOP) in pain transmission is controversial. It seems to be pronociceptive when given supraspinally, but elicits an antinociceptive action when injected spinally. Here, we examined whether the N/OFQ system plays a role in experimentally induced pruritus. Scratching behavior was produced by intradermal administration of serotonin (50 mu g/50 mu l/mouse) or nociceptin (30 nmol/50 mu l/mouse) to Balb/c mice. JTC-801 (1, 3 or 10 mg/kg, i.p.), a NOP receptor antagonist, attenuated both serotonin- and nociceptin-induced scratches. When given intradermally, JTC-801 (100 nmol) significantly reduced serotonin-induced but not nociceptin-induced scratches. We propose that antagonizing NOP receptors either systemically or localy may be a novel approach in the development of antipruritic agents.
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    Involvement of Descending Serotonergic and Noradrenergic Systems and their Spinal Receptor Subtypes in the Antinociceptive Effect of Dipyrone
    (Georg Thieme Verlag Kg, 2015) Gencer, A.; Gunduz, O.; Ulugol, A.
    The antinociceptive effect of dipyrone is partly due to its action upon pain-related central nervous system structures. Despite intensive research, the precise mechanisms mediating its analgesic effects remain unclear. Here, we aimed to determine whether neurotoxic destruction of descending inhibitory pathways affect dipyrone-induced antinociception and whether various spinal serotonergic and adrenergic receptors are involved in this antinociception. The nociceptive response was assessed by the tail-flick test. Mice injected with dipyrone (150, 300, 600 mg/kg, i. p.) elicited dose-related antinociception. The neurotoxins 5,7-dihydroxytryptamine (50 mu g/mouse) and 6-hydroxydopamine (20 mu g/mouse) are applied intrathecally to deplete serotonin and noradrenaline in the spinal cord. 3 days after neurotoxin injections, a significant reduction in the antinociceptive effect of dipyrone was observed. Intrathecal administration of monoaminergic antagonists (10 mu g/mouse), the 5-HT2a antagonist ketanserin, the 5-HT3 antagonist ondansetron, the 5-HT7 antagonist SB-258719, alpha(1)-adrenoceptor antagonist prazosin, alpha(2)-adrenoceptor antagonist yohimbine, and the beta-adrenoceptor antagonist propranolol also attenuated dipyrone antinociception. We propose that descending serotonergic and noradrenergic pathways play pivotal role in dipyrone-induced antinociception and spinal 5-HT2a, 5-HT3, and 5-HT7-serotonergic and alpha(1), alpha(2), and beta-adrenergic receptors mediate this effect.
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    Involvement of spinal cannabinoid receptors in the antipruritic effects of WIN 55,212-2, a cannabinoid receptor agonist
    (Wiley, 2018) Bilir, K. A.; Anli, G.; Ozkan, E.; Gunduz, O.; Ulugol, A.
    Background. Cannabinoids have been used for their analgesic and euphoric effects for millennia, but recently the antipruritic effects of cannabis have been discovered. Considering the similarities between pain and itch sensations, we hypothesized that cannabinoid receptors may play a role in the antipruritic effects of cannabinoids. Aim. To analyse the role of the spinal cannabinoid receptors, CB1 and CB2, in the antipruritic effects of the cannabinoid agonist WIN 55,212-2. Methods. Male Balb/c mice weighing 20-30 g were used. Scratching behaviour in the mice was produced by injection of serotonin 5 g/50 L intradermally into the nape of the neck. Scratching of the site of injection by the hind paws was video-recorded for 30 min. After testing different doses of WIN 55,212-2 [1, 3 and 10 mg/kg intraperitoneally (IP)], the effects of the CB1 receptor antagonist, AM-251 [1 g/mouse administered intrathecally (IT)] and the CB2 receptor antagonist AM-630 (4 g/mouse IT) on the antipruritic effects of WIN 55,212-2 were studied using a rotarod apparatus. Results. WIN 55,212-2 (1, 3 or 10 mg/kg IP) dose-dependently decreased serotonin-induced scratches. The receptor antagonist CB1 partially reversed the effects of WIN 55,212-2 (P < 0.05); whereas CB2 had no statistically significant effect. WIN 55,212-2 impaired motor function only at the highest dose given (10 mg/kg, P < 0.05). Conclusions. Our findings support prior researches indicating that cannabinoids exert antipruritic effects. Moreover, our results show that the antipruritic effects of cannabinoids are partially mediated by spinal CB1 receptors.