Browsing by Author "Carroll, F. Ivy"
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Item Expression and pharmacological modulation of visceral pain-induced conditioned place aversion in mice(Elsevier, 2016-03) Muldoon, Pretal P.; AiSharari, Shakir; Carroll, F. Ivy; Negus, S. Stevens; Damaj, M. Imad; Bağdaş, Deniz; Uludağ Üniversitesi/Tıp Fakültesi/Deney Hayvanları Yetiştirme ve Araştırma Merkezi.; 15062425700Pain encompasses both a sensory as well as an affective dimension and these are differentially processed in the brain and periphery. It is therefore important to develop animal models to reflect the non-reflexive assays in pain. In this study, we compared effects of the mu opioid receptor agonist morphine, the nonsteroidal anti-inflammatory drug ketoprofen and the kappa receptor opioid agonist U50,488H and antagonist JDTic on acetic acid-induced stretching and acetic acid-induced aversion in the condition place aversion (CPA) test in male ICR mice. Intraperitoneal administration of acetic acid (0.32-1%) was equipotent in stimulating stretching and CPA. Ketoprofen, morphine and U50,488H all inhibited the acid induced stretching. Ketoprofen and morphine also blocked the acid-induced CPA but U50,488H failed to do so. The reversal ability of ketoprofen and morphine on acid-induced CPA is unique to pain-stimulated place aversion since these drugs failed to reduce non-noxious LiCl-induced CPA. Overall, this study characterized and validated a preclinical mouse model of pain-related aversive behavior that can be used to assess genetic and biological mechanisms of pain as well as improving the predictive validity of preclinical studies on candidate analgesics.Item In vivo interactions between alpha 7 nicotinic acetylcholine receptor and nuclear peroxisome proliferator-activated receptor-alpha: Implication for nicotine dependence(Elsevier, 2017-03-04) Jackson, Asti; Muldoon, Pretal P.; Lichtman, Aron H.; Carroll, F. Ivy; Greenwald, Mark; Miles, Michael F.; Damaj, M. Imad; Bağdaş, Deniz; Uludağ Üniversitesi/Tıp Fakültesi/Deney Hayvanları Yetiştirme ve Araştırma Merkezi.; 15062425700Chronic tobacco use dramatically increases health burdens and financial costs. Limitations of current smoking cessation therapies indicate the need for improved molecular targets. The main addictive component of tobacco, nicotine, exerts its dependency effects via nicotinic acetylcholine receptors (nAChRs). Activation of the homomeric alpha 7 nAChR reduces nicotine's rewarding properties in conditioned place preference (CPP) test and i.v. self-administration models, but the mechanism underlying these effects is unknown. Recently, the nuclear receptor peroxisome proliferator-activated receptor type-alpha (PPAR alpha) has been implicated as a downstream signaling target of the alpha 7 nAChR in ventral tegmental area dopamine cells. The present study investigated PPAR alpha as a possible mediator of the effect of alpha 7 nAChR activation in nicotine dependence. Our results demonstrate the PPAR alpha antagonist GW6471 blocks actions of the alpha 7 nAChR agonist PNU282987 on nicotine reward in an unbiased CPP test in male ICR adult mice. These findings suggests that alpha 7 nAChR activation attenuates nicotine CPP in a PPAR alpha-dependent manner. To evaluate PPAR alpha activation in nicotine dependence we used the selective and potent PPAR alpha agonist, WY-14643 and the clinically used PPAR alpha activator, fenofibrate, in nicotine CPP and we observed attenuation of nicotine preference, but fenofibrate was less potent. We also studied PPAR alpha in nicotine dependence by evaluating its activation in nicotine withdrawal. WY-14643 reversed nicotine withdrawal signs whereas fenofibrate had modest efficacy. This suggests that PPAR alpha plays a role in nicotine reward and withdrawal and that further studies are warranted to elucidate its function in mediating the effects of alpha 7 nAChRs in nicotine dependence.Item The interaction between alpha 7 nicotinic acetylcholine receptor and nuclear peroxisome proliferator-activated receptor-alpha represents a new antinociceptive signaling pathway in mice(Elsevier, 2017-06-08) Donvito, Giulia; Toma, Wisam; Rahimpour, Elnaz; Jackson, Asti; Meade, Julie A.; Alsharari, Shakir; Kulkarni, Abhijit R.; Carroll, F. Ivy; Lichtman, Aron H.; Papke, Roger L; Thakur, Ganesh A.; Damaj, M. Imad; Bağdaş, Deniz; Uludağ Üniversitesi/Tıp Fakültesi/Deney Hayvanları Yetiştirme ve Araştırma Merkezi.; 15062425700Recently, alpha 7 nicotinic acetylcholine receptors (nAChRs), primarily activated by binding of orthosteric agonists, represent a target for anti-inflammatory and analgesic drug development. These receptors may also be modulated by positive allosteric modulators (PAMs), ago-allosteric ligands (ago-PAMs), and alpha 7-silent agonists. Activation of 00 nAChRs has been reported to increase the brain levels of endogenous ligands for nuclear peroxisome proliferator-activated receptors type-alpha (PPAR-alpha), palmitoylethanolamide (PEA) and oleoylethanolamide (OEA), in a Ca2+-dependent manner. Here, we investigated potential crosstalk between alpha 7 nAChR and PPAR-alpha, using the formalin test, a mouse model of tonic pain. Using pharmacological and genetic approaches, we found that PNU282987, a full alpha 7 agonist, attenuated formalin-induced nociceptive behavior in alpha 7 -dependent manner. Interestingly, the selective PPAR-alpha antagonist GW6471 blocked the antinociceptive effects of PNU282987, but did not alter the antinociceptive responses evoked by the alpha 7 nAChR PAM PNU120596, ago-PAM GAT107, and silent agonist NS6740. Moreover, GW6471 administered systemically or spinally, but not via the intraplantar surface of the formalin-injected paw blocked PNU282987-induced antinociception. Conversely, exogenous administration of the naturally occurring PPAR-alpha agonist PEA potentiated the antinociceptive effects of PNU282987. In contrast, the cannabinoid 031 antagonist rimonabant and the CB2 antagonist SR144528 failed to reverse the antinociceptive effects of PNU282987. These findings suggest that PPAR-alpha plays a key role in a putative antinociceptive alpha 7 nicotinic signaling pathway.Item Sex differences and drug dose influence the role of the alpha 7 nicotinic acetylcholine receptor in the mouse dextran sodium sulfate-induced colitis model(Oxford University, 2017) Alsharari, Shakir D.; Akbarali, Hamid I.; Lichtman, Patraic A.; Raborn, Erinn S.; Cabral, Guy A.; Carroll, F. Ivy; McGee, Elizabeth A.; Damaj, M. Imad; Bağdaş, Deniz; Uludağ Üniversitesi/Tıp Fakültesi/Deney Hayvanları Yetiştiriciliği ve Araştırma Merkezi.; 15062425700Introduction: alpha 7 nicotinic acetylcholine receptors (nAChRs) play an important role in vagus nerve-based cholinergic anti-inflammatory effects. This study was designed to assess the role of alpha 7 nAChRs in dextran sodium sulfate (DSS)-induced colitis in male and female mouse. We first compared disease activity and pathogenesis of colitis in alpha 7 knockout and wild-type mice. We then evaluated the effect of several alpha 7 direct and indirect agonists on the severity of disease in the DSS-induced colitis. Methods: Male and female adult mice were administered 2.5% DSS solution freely in the drinking water for 7 consecutive days and the colitis severity (disease activity index) was evaluated as well as colon length, colon histology, and levels of tumor necrosis factor-alpha colonic levels. Results: Male, but not female, alpha 7 knockout mice displayed a significantly increased colitis severity and higher tumor necrosis factor-alpha levels as compared with their littermate wild-type mice. Moreover, pretreatment with selective alpha 7 ligands PHA-543613, choline, and PNU-120596 decreased colitis severity in male but not female mice. The anti-colitis effects of these alpha 7 compounds dissipated when administered at higher doses. Conclusions: Our results suggest the presence of a alpha 7-dependent anti-colitis endogenous tone in male mice. Finally, our results show for the first time that female mice are less sensitive to the anticolitis activity of alpha 7 agonists. Ovarian hormones may play a key role in the sex difference effect of alpha 7 nAChRs modulation of colitis in the mouse. Implications: Our collective results suggest that targeting alpha 7 nAChRs could represent a viable therapeutic approach for intestinal inflammation diseases such as ulcerative colitis with the consideration of sex differences.