title: Changes in nociceptin/orphanin FQ levels in rat brain regions after acute and chronic cannabinoid treatment in conjunction with the development of antinociceptive tolerance.
abstract: 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.
authors.affiliation: Department of Medical Pharmacology, Faculty of Medicine, Trakya University, 22030, Edirne, Turkey.
authors.forename: Ahmet
authors.initials: A
authors.lastname: Ulugol
authors.affiliation: Department of Medical Pharmacology, Faculty of Medicine, Trakya University, 22030, Edirne, Turkey.
authors.forename: Ruhan D
authors.initials: RD
authors.lastname: Topuz
authors.affiliation: Department of Medical Pharmacology, Faculty of Medicine, Trakya University, 22030, Edirne, Turkey.
authors.forename: Ozgur
authors.initials: O
authors.lastname: Gunduz
authors.affiliation: Department of Histology and Embryology, Faculty of Medicine, Trakya University, 22030, Edirne, Turkey.
authors.forename: Gulnur
authors.initials: G
authors.lastname: Kizilay
authors.affiliation: Department of Medical Pharmacology, Faculty of Medicine, Trakya University, 22030, Edirne, Turkey.
authors.forename: Hakan C
authors.initials: HC
authors.lastname: Karadag
mesh_terms: D000634:Aminoquinolines / Q000494:pharmacology; D000700:Analgesics / Q000494:pharmacology*; D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D048588:Benzoxazines / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002186:Cannabinoids / Q000494:pharmacology*; D004361:Drug Tolerance / Q000502:physiology*; D008297:Male; D009020:Morphine / Q000494:pharmacology; D009025:Morpholines / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology*; D018847:Opioid Peptides / Q000378:metabolism*; D010146:Pain / Q000188:drug therapy; D010147:Pain Measurement / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D011957:Receptors, Opioid / Q000378:metabolism; D000097629:Nociceptin
chemical_list: D000634:Aminoquinolines; D000700:Analgesics; D000701:Analgesics, Opioid; D001549:Benzamides; D048588:Benzoxazines; D002186:Cannabinoids; D009020:Morphine; D009025:Morpholines; D009281:Naphthalenes; D009292:Narcotic Antagonists; D018847:Opioid Peptides; D011957:Receptors, Opioid; D000097629:Nociceptin; C433236:N-(4-amino-2-methylquinolin-6-yl)-2-(4-ethylphenoxymethyl)benzamide; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone
keywords: Western blotting; antinociceptive effect; cannabinoid; immunohistochemistry; nociceptin/orphanin FQ; tolerance