Orexin A induced increases in rat locus coeruleus neuronal activity are attenuated by systemic administration of OX1R and OX2R antagonists

Medicine in Drug Discovery

Gary Gilmour¹  Christopher M. Holton²  Keith A. Wafford³ 

[1] Eli Lilly and Company, Erl Wood Manor, Windlesham, Surrey GU20 6PH, United Kingdom;Corresponding author.;Eli Lilly and Company, Erl Wood Manor, Windlesham, Surrey GU20 6PH, United Kingdom;

关键词: Orexin;    hypocretin;    locus coeruleus;    rat;    pharmacokinetics;   

DOI  :  

来源: DOAJ

【 摘 要 】

Since the initial characterisation of the orexin/hypocretin system, the noradrenergic locus coeruleus (LC) has been a key focus due to its high expression of orexin receptors. Direct application of orexin A (OX-A) into the LC increases neural activity, and consequently arousal, attention and analgesia. We administered OX-A intracerebroventricularly to anaesthetised male CD® IGS rats and recorded spontaneous neural activity in the LC, blood pressure and heart rate. We then pre-treated with systemically administered orexin receptor 1 (OX1R) or orexin receptor 2 (OX2R) antagonists, SB-334867 and LSN2424100 respectively, and measured any changes in OX-A-induced effects. Central OX-A exposure dose dependently activated LC neurons over the period of 1 h: OX-A at 600 and 63 pmol, but not 20 pmol, increased neural activity. OX-A at 600 pmol, but not 63 or 20 pmol, altered blood pressure. OX-A did not alter heart rate at any of the doses tested. Pre-treatment with either OX1R or OX2R antagonist attenuated the OX-A-induced increase in LC firing with OX2R antagonism having a delayed onset. Neither antagonists altered LC firing on their own. We show that LC activation can be modulated by both OX1R and OX2R mechanisms, despite low OX2R expression in the LC. The LC is a key target brain nucleus in disease mechanisms that could be modulated by orexinergic pharmacology.

【 授权许可】

Unknown