Browsing by Author "Damaj, Mohamad Imad"
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Item Diacylglycerol lipase beta inhibition reverses nociceptive behaviour in mouse models of inflammatory and neuropathic pain(Wiley, 2016-02-16) Wilkerson, Jenny L.; Ghosh, Sudeshna; Mason, Brittany L.; Crowe, Molly S.; Hsu, Kulung; Wise, Laura E.; Kinsey, Steven G.; Damaj, Mohamad Imad; Cravatt, Benjamin F.; Lichtman, Aron H.; Baǧdaş, Deniz; Uludağ Üniversitesi/Tıp Fakültesi/Deney Hayvanları Yetiştirme ve Araştırma Merkezi.; 15062425700Background and PurposeInhibition of diacylglycerol lipase (DGL) prevents LPS-induced pro-inflammatory responses in mouse peritoneal macrophages. Thus, the present study tested whether DGL inhibition reverses allodynic responses of mice in the LPS model of inflammatory pain, as well as in neuropathic pain models. Experimental ApproachInitial experiments examined the cellular expression of DGL and inflammatory mediators within the LPS-injected paw pad. DAGL- (-/-) mice or wild-type mice treated with the DGL inhibitor KT109 were assessed in the LPS model of inflammatory pain. Additional studies examined the locus of action for KT109-induced antinociception, its efficacy in chronic constrictive injury (CCI) of sciatic nerve and chemotherapy-induced neuropathic pain (CINP) models. Key ResultsIntraplantar LPS evoked mechanical allodynia that was associated with increased expression of DGL, which was co-localized with increased TNF- and prostaglandins in paws. DAGL- (-/-) mice or KT109-treated wild-type mice displayed reductions in LPS-induced allodynia. Repeated KT109 administration prevented the expression of LPS-induced allodynia, without evidence of tolerance. Intraplantar injection of KT109 into the LPS-treated paw, but not the contralateral paw, reversed the allodynic responses. However, i.c.v. or i.t. administration of KT109 did not alter LPS-induced allodynia. Finally, KT109 also reversed allodynia in the CCI and CINP models and lacked discernible side effects (e.g. gross motor deficits, anxiogenic behaviour or gastric ulcers). Conclusions and ImplicationsThese findings suggest that local inhibition of DGL at the site of inflammation represents a novel avenue to treat pathological pain, with no apparent untoward side effects.Item Effects of methoxsalen, a CYP2A5/6 inhibitor, on nicotine dependence behaviors in mice(Pergamon-Elsevier, 2014-10) Zhu, Andy Z.X; Muldoon, Pretal P.; Tyndale, Rachel F.; Damaj, Mohamad Imad; Bağdaş, Deniz; Uludağ Üniversitesi/Tıp Fakültesi/Deney Hayvanları Yetiştirme ve Araştırma Birimi.; 15062425700Metabolism of nicotine to inactive cotinine by hepatic enzyme CYP2A6 is the principal pathway by which active nicotine is removed from circulation. We therefore hypothesized that inhibition of mouse CYP2A5, the ortolog of human CYP2A6, by methoxsalen (8-methoxypsoralen) alter dependence-related behaviors of nicotine in the mouse. Conditioned place preference (CPP) test was used to assess the appetitive reward-like properties and precipitated nicotine withdrawal to assess physical (somatic and hyperalgesia) and affective (anxiety-related behaviors) measures. The nicotine plasma levels were also measured with or without methoxsalen pretreatment. Methoxsalen (15 and 30 mg/kg, intraperitoneally) pretreatment enhanced nicotine-induced preference in mice (p < 0.05). However, there was a lack of enhancement of nicotine in the CPP test after the highest dose of the CYP-2A5 inhibitor. Similarly to the CPP results, repeated administration of methoxsalen increased the intensity of mecamylamine-precipitated withdrawal signs. The potentiation of nicotine preference and withdrawal intensity by methoxsalen was accompanied by significant increase in nicotine plasma levels in mice (p < 0.05). Finally, methoxsalen enhanced the ability of a very low dose of nicotine (0.05 mg/kg) to reverse withdrawal signs in mice undergoing spontaneous withdrawal after chronic nicotine infusion (p < 0.05). In conclusion, inhibition of nicotine metabolism by methoxsalen alters the behavioral effects of nicotine in the mouse. Combining CYP2A6 inhibitors with low dose nicotine replacement therapies may have a beneficial role in smoking cessation because it will decrease the drug elimination rate and maintain plasma and brain nicotine levels.Item Nicotinic receptors as targets for novel analgesics and anti-infl ammatory drugs(Humana Press Inc, 2014) Damaj, Mohamad Imad; Freitas, Kelen C.C.; Flood, Pamela Dru; Lester, R. A. J.; Baǧdaş, Deniz; Uludağ Üniversitesi/Tıp Fakültesi/Deney Hayvanları Yetiştirme ve Araştırma Merkezi.; 15062425700Nicotine and nicotinic receptors have been explored for the past three decades as a strategy for pain control. These receptors are widely expressed throughout the central and peripheral nervous system as well as immune cells. Despite encouraging results with many selective alpha 4 beta 2* agonists in animal models of pain, human studies showed a narrow therapeutic window between analgesic efficacy and toxicity is associated with the use of these agonists as analgesics. alpha 4 beta 2 positive allosteric modulators are being developed with the aim to increase the potency or therapeutic window of these agonists. However, several recent developments have potentially opened new windows of opportunity in the use of nicotinic agents for analgesia. Accumulating evidences suggest that alpha 7 agonists and positive allosteric modulators hold a lot of promise in the treatment of chronic inflammatory pain conditions. In addition, recent animal studies suggest the therapeutic potential of ligands acting at other subtypes of nicotinic receptors. The current review will attempt to highlight these recent developments and outline some important findings that demonstrate further potential for the development of nicotinic ligands as novel analgesics.