CNS opioid signaling separates CB1 mediated effects on body weight and mood-related behaviour in mice

CNS opioid signaling separates CB1 mediated effects on body weight and mood-related behaviour in mice

S42 Oral Abstracts O58 O59 CNS opioid signaling separates CB1 mediated effects on body weight and mood-related behaviour in mice High fat diet fe...

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S42

Oral Abstracts

O58

O59

CNS opioid signaling separates CB1 mediated effects on body weight and mood-related behaviour in mice

High fat diet feeding switches the second messenger system activated by leptin on vagal afferents

Lockie 1,4,∗ ,

Czyzyk 2 ,

Chaudhary 1 ,

S.H. T.A. N. D. Perez-Tilve 1 , S.C. Woods 3 , B.J. Oldfield 4 , M.A. Statnick 2 , M.H. Tschöp 1 1 Metabolic

Diseases Institute, Div. of Endocrinology, Department of Medicine and 2 Eli Lilly and Co, Indianapolis, IN, USA 3 Department of Psychiatry, University of Cincinnati, Cincinnati, OH, USA 4 Department of Physiology, Monash University, Clayton, Vic, Australia Aim: Existing monotherapies for the treatment of obesity provide only modest weight loss and/or have adverse side effects and this is also the case with the CB1 receptor inverse agonist, rimonabant. We aimed to investigate the possibility of improving efficacy and reducing side effects of rimonabant by co-treatment with opioid system antagonists. Method: Using both genetic and pharmacological removal of opioid signaling in mice, we investigated changes in body weight, food intake and fat mass as well as behavioral outcomes of interactions between opioid ligands and the cannabinoid receptor 1 (CB1) using the inverse agonist, rimonabant. Results: The ability of rimonabant to reduce weight is enhanced by removal of with mu opioid receptor (MOR) signalling, while not being greatly affected by kappa (KOR) opioid receptor blockade. Additionally, lack of opioid signaling, especially KOR, attenuated the ability of rimonabant to decrease immobility time in the Porsolt forced-swim test, a preclinical model of depression. Conclusion: These results indicate that the endogenous opioid system is involved in modulating both the metabolic and mood effects of rimonabant. Conflict of interest: TAC and MAS were employees of Eli Lilly and Co at the time of the research. doi:10.1016/j.orcp.2011.08.136

S.J. Kentish 2,∗ , T.A. O’Donnell 1 , G. Wittert 2 , L.A. Blackshaw 1,2,3 , A.J. Page 1,2,3 1 Nerve-Gut

Research Laboratory, Room 1-216-H, Level 1, Hanson Institute, Royal Adelaide Hospital, Australia 2 Discipline of Medicine, University of Adelaide, Adelaide, Australia 3 Discipline of Physiology, University of Adelaide, Adelaide, Australia

Aim: Leptin potentiates responses of gastric mucosal receptors, but after a high fat diet (HFD) inhibits responses of gastric tension receptors to mechanical stimulation (DDW 2011). Activation of different second messenger pathways may explain this switch in effect and thus we aimed to determine the signalling pathways used by leptin on gastric vagal afferents. Methods: C57/BL6 mice were placed on either a standard laboratory diet (SLD) or HFD for 12 weeks. Single fibre recordings of vagal mechanoreceptors were obtained (J Neurophysiol 2002;87:2095). It was determined if antagonists to suspected second messengers could prevent the effect of leptin. Results: In SLD mice, leptin (10 nM) increased the response of mucosal receptors to mucosal stroking with von Frey hairs (10—1000 mg; P < 0.001). This effect was blocked by inhibitors to the following second messengers: JAK2 (AG490;5 ␮M), PI3K (wortmannin;5 nM), PDE3 (cilostamide;5 ␮M), PLC (U73122;10 ␮M), TRPC channel (2-APB;10 ␮M). This suggests leptin activates this series of molecules to in turn activate the TRPC channel. In HFD mice, leptin reduced the response of tension receptors to circular tension (1—5 g; P < 0.001). This effect was blocked by AG490 and wortmannin, but not cilostamide, U73122 or 2-APB indicating a divergence in the second messenger system. The BKCa channel blocker, iberiotoxin (100 nM), abolished the effect of leptin on tension receptors. Conclusion: The second messenger pathway used by leptin depends not only on diet but also gastric afferent subclasses. These changes are likely to occur in the development of obesity and are consistent with leptin’s inability to effectively reduce food intake in obesity. Supported by University of Adelaide and NHMRC Australia. Conflict of interest: None. doi:10.1016/j.orcp.2011.08.137