Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC, 3052, Australia.
ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Parkville, VIC, Australia.
Cell Mol Life Sci. 2019 Aug;76(15):3033-3050. doi: 10.1007/s00018-019-03077-6. Epub 2019 Mar 23.
The use of opioid analgesics is severely limited due to the development of intractable constipation, mediated through activation of mu opioid receptors (MOR) expressed by enteric neurons. The related delta opioid receptor (DOR) is an emerging therapeutic target for chronic pain, depression and anxiety. Whether DOR agonists also promote sustained inhibition of colonic transit is unknown. This study examined acute and chronic tolerance to SNC80 and ARM390, which were full and partial DOR agonists in neural pathways controlling colonic motility, respectively. Excitatory pathways developed acute and chronic tolerance to SNC80, whereas only chronic tolerance developed in inhibitory pathways. Both pathways remained functional after acute or chronic ARM390 exposure. Propagating colonic motor patterns were significantly reduced after acute or chronic SNC80 treatment, but not by ARM390 pre-treatment. These findings demonstrate that SNC80 has a prolonged inhibitory effect on propagating colonic motility. ARM390 had no effect on motor patterns and thus may have fewer gastrointestinal side-effects.
由于阿片类镇痛药的使用受到严重限制，因为其通过激活表达于肠神经元的μ阿片受体（MOR）而产生难治性便秘。相关的δ阿片受体（DOR）是治疗慢性疼痛、抑郁和焦虑的新兴靶点。DOR 激动剂是否也促进结肠转运的持续抑制尚不清楚。本研究检测了 SNC80 和 ARM390 的急性和慢性耐受，它们分别是控制结肠运动的神经通路中完全和部分 DOR 激动剂。兴奋性通路对 SNC80 产生急性和慢性耐受，而抑制性通路仅产生慢性耐受。两条通路在急性或慢性 ARM390 暴露后仍保持功能。急性或慢性 SNC80 处理后，传播性结肠运动模式显著减少，但 ARM390 预处理则无此作用。这些发现表明 SNC80 对传播性结肠运动具有延长的抑制作用。ARM390 对运动模式没有影响，因此可能具有较少的胃肠道副作用。
