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    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.
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    The Role of Hydrogen Sulfide in the Development of Tolerance and Dependence to Morphine in Mice
    (Karger, 2021) Cetin, Zeynep; Gunduz, Ozgur; Topuz, Ruhan D.; Dokmeci, Dikmen; Karadag, Hakan C.; Ulugol, Ahmet
    Objective: Hydrogen sulfide is an endogenous gaseous mediator that has been indicated to have a role in pain mechanisms. In this study, we aimed to detect brain and spinal cord hydrogen sulfide levels during different phases of tolerance and dependence to morphine and to determine the effects of inhibition of endogenous hydrogen sulfide production on the development of tolerance and dependence. Methods: Morphine tolerance and dependence was developed by subcutaneous injection of morphine (10 mg/kg) twice daily for 12 days. Physical dependence was determined by counting the jumps for 20 min, which is a withdrawal symptom occurring after a single dose of naloxone (5 mg/kg) administered intraperitoneally (i.p.). Propargylglycine (30 mg/kg, i.p.), a cystathionine-gamma-lyase inhibitor, and hydroxylamine (12.5 mg/kg, i.p.), a cystathionine-beta-synthase inhibitor, were used as hydrogen sulfide synthase inhibitors. The tail-flick and hot-plate tests were used to determine the loss of antinociceptive effects of morphine and development of tolerance. Results: It was found that chronic and acute uses of both propargylglycine and hydroxylamine prevented the development of tolerance to morphine, whereas they had no effect on morphine dependence. Chronic and acute administrations of hydrogen sulfide synthase inhibitors did not exert any difference in hydrogen sulfide levels in brain and spinal cords of both morphine-tolerant and -dependent animals. Conclusion: It has been concluded that hydrogen sulfide synthase inhibitors may have utility in preventing morphine tolerance.
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    Synergistic anti-allodynic effects of nociceptin/orphanin FQ and cannabinoid systems in neuropathic mice
    (Pergamon-Elsevier Science Ltd, 2011) Gunduz, Ozgur; Karadag, Hakan C.; Ulugol, Ahmet
    Combinations of analgesics from different classes are commonly used in the management of chronic pain. The goal is to enhance pain relief together with the reduction of side effects. The present study was undertaken to examine the anti-allodynic synergy resulting from the combination of WIN 55,212-2, a cannabinoid CBI receptor agonist, and JTC-801, a nociceptin/orphanin FQ receptor antagonist, on neuropathic pain. Mice were tested for behavioral effects before and 2-4 weeks after the surgery, in which a partial tight ligation of the sciatic nerve was made. Nerve injury-induced mechanical allodynia was assessed with Dynamic Plantar Aesthesiometer, and a hot/cold plate was used to assess cold allodynia. Both WIN 55,212-2 and JTC-801 produced dose-dependent mechanical and cold anti-allodynic effects. As shown by isobolographic analysis, WIN 55,212-2/JTC-801 combinations interacted synergistically at all three ratios studied in the mechanical allodynia assay. In conclusion, co-administration of a cannabinoid with a nociceptin/orphanin FQ receptor antagonist resulted in a synergistic interaction, which may have utility in the pharmacological treatment of neuropathic pain. (C) 2011 Elsevier Inc. All rights reserved.