双重激动痛敏素受体/μ阿片受体的镇痛与成瘾的特征及机制研究

Neuropathic pain involves the complex neuroplasticity of peripheral and central nervous system. Because the existing analgesic agents can’t achieve the desired therapeutic effect, the treatment for neuropathic pain is very difficult. Opioid analgesics, such as morphine, produce good analgesia when used initially; however, prolonged use of the opioid analgesics induce tolerance rapidly and iatrogenic addiction. Nociceptin/orphanin FQ receptor (NOP receptor) belongs to the family of opioid receptors. Recently, some studies showed that the activation of NOP receptor not only enhances µ opioid receptor (MOP receptor)-induced analgesia, but also antagonizes MOP receptor-induced addiction, which indicates that dual activation of NOP and MOP receptors may be a novel potential target for discovering potent and low-addictive analgesic agents. However, under the neuropathic pain condition, the characteristics and the mechanisms of NOP receptor affecting MOP receptor-induced analgesic actions, especially analgesic tolerance, and addiction remains unclear. For neuropathic pain, therefore, this project will investigate the effects of activating NOP receptor on the analgesia, tolerance and addiction mediated by MOP receptor, as well as the cellular and molecular mechanisms, to confirming dual-activation of NOP and MOP receptors as a novel potential target for potent analgesic agents with low tolerance and addiction. In addiction, some novel structural bi-functional agonists of NOP/MOP receptors with higher selectivity to the NOP receptor will be obtained, which is helpful to discover the ideal analgesic agent.

神经病理性疼痛涉及外周及中枢神经系统复杂的可塑性变化，现有镇痛药效果不佳，治疗极为棘手。阿片类镇痛药（如吗啡）初期对神经病理性疼痛具有良好的镇痛作用，但反复使用迅速产生镇痛耐受及医源性成瘾。痛敏素受体（NOP受体）属阿片受体家族，有研究显示急性疼痛下，激动NOP受体增强µ阿片受体（MOP受体）镇痛、对抗成瘾，提示双重激动NOP/MOP受体可能成为新型镇痛药研发的潜在靶标。但在神经病理性疼痛状态下，NOP受体影响MOP受体镇痛（特别是镇痛耐受）与成瘾的特点及机制尚不清楚。本项目拟在我们前期基础上，针对神经病理性疼痛，以新型双功能激动剂为探针，系统研究激动NOP受体对MOP受体介导的镇痛、耐受及成瘾的影响及其机制，确证双重激动NOP/MOP受体作为低耐受、低成瘾的强效镇痛药研发候选靶标的潜力；同时获得结构新颖、NOP受体选择性更好的NOP/MOP受体双功能激动剂，为寻找理想镇痛药奠定基础。

神经病理性疼痛涉及外周及中枢神经系统复杂的可塑性变化，现有镇痛药效果不佳，治疗 极为棘手。阿片类镇痛药（如吗啡）初期对神经病理性疼痛具有良好的镇痛作用，但反复使用迅速产生镇痛耐受及医源性成瘾。痛敏素受体（NOP受体）属阿片受体家族，有研究提示显急性疼痛下双重激动NOP/MOP受体可能成为新型镇痛药研发的潜在靶标。但在神经病理性疼痛状态下，NOP受体影响MOP受体镇痛与成瘾的特点及机制尚不清楚。本项目发现在小鼠坐骨神经分支损伤（SNI）所致神经病理性疼痛模型中，双重激动NOP/MOP受体与单独激动MOP受体一样能够产生完全镇痛作用，但连续激动的镇痛耐受性、躯体依赖性和正性强化效应均低于单独激动MOP受体，提示依赖性和成瘾潜能较低。因此，针对神经病理性疼痛，双重激动NOP/MOP受体具备低耐受、低成瘾性的强效镇痛药研发的候选靶标的潜力。另外，项目完成了新型NOP/MOP受体双功能激动剂的研究，发现在小鼠SNI致神经痛模型中新化合物具有强效镇痛作用、且由激动NOP受体和MOP受体共同介导，镇痛效能可达完全镇痛、持续时间至少8 h，镇痛效价高于吗啡和标杆化合物，连续给药镇痛耐受性较低（低于吗啡和标杆化合物）；本研究条件下无躯体依赖潜能，急性奖赏效应低于吗啡和标杆化合物、且无正性强化效应，提示成瘾潜能较低。因此新型NOP/MOP受体双功能激动剂对神经病理性疼痛具有强效、完全、长时间的镇痛作用，耐受性、依赖性和成瘾潜能较低，为寻找理想的镇痛药奠定了基础。