Smeester Branden A, Lunzer Mary M, Akgün Eyup, Beitz Alvin J, Portoghese Philip S
Department of Veterinary and Biomedical Sciences, College of Veterinary Medicine, University of Minnesota, St. Paul, MN 55108, United States.
Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, United States.
Eur J Pharmacol. 2014 Nov 15;743:48-52. doi: 10.1016/j.ejphar.2014.09.008. Epub 2014 Sep 17.
The therapeutic management of chronic pain associated with many cancers is problematic due to the development of tolerance and other adverse effects during the disease progression. Recently we reported on a bivalent ligand (MMG22) containing both mu agonist and mGluR5 antagonist pharmacophores that produced potent antinociception in mice with LPS-induced acute inflammatory pain via a putative MOR-mGluR5 heteromer. In the present study we have investigated the antinociception of MMG22 in a mouse model of bone cancer pain to determine its effectiveness in reducing this type of chronic nociception. There was a 572-fold increase in the potency of MMG22 over a period of 3-21 days that correlated with the progressive increase in hyperalgesia induced by bone tumor growth following implantation of fibrosarcoma cells in mice. The enhancement of antinociception with the progression of the cancer is possibly due to inhibition of NMDA receptor-mediated hyperalgesia via antagonism of mGluR5 and concomitant activation of MOR by the MMG22-occupied heteromer. Notably, MMG22 was 3.6-million-fold more potent than morphine at PID 21. Since MMG22 exhibited a 250,000-times greater potency than that of a mixture of the mu opioid (M19) agonist and mGluR5 antagonist (MG20) monovalent ligands, the data suggest that targeting the putative MOR-mGluR5 heteromer is far superior to univalent interaction with receptors in reducing tumor-induced nociception. In view of the high potency, long duration (>24h) of action and minimal side effects, MMG22 has the potential to be a superior pharmacological agent than morphine and other opiates in the treatment of chronic cancer pain and to serve as a novel pharmacologic tool.
由于在疾病进展过程中会产生耐受性和其他不良反应，许多癌症相关的慢性疼痛的治疗管理存在问题。最近，我们报道了一种二价配体（MMG22），它同时含有μ激动剂和mGluR5拮抗剂药效基团，通过假定的MOR-mGluR5异聚体在脂多糖诱导的急性炎症性疼痛小鼠中产生强效镇痛作用。在本研究中，我们研究了MMG22在骨癌疼痛小鼠模型中的镇痛作用，以确定其在减轻这种慢性伤害感受方面的有效性。在3-21天的时间里，MMG22的效力增加了572倍，这与小鼠植入纤维肉瘤细胞后骨肿瘤生长诱导的痛觉过敏的逐渐增加相关。随着癌症进展镇痛作用增强，可能是由于MMG22占据的异聚体通过拮抗mGluR5抑制NMDA受体介导的痛觉过敏，并同时激活MOR。值得注意的是，在第21天，MMG22的效力比吗啡高360万倍。由于MMG22的效力比μ阿片类（M19）激动剂和mGluR5拮抗剂（MG20）单价配体混合物高25万倍，数据表明，在减少肿瘤诱导的伤害感受方面，靶向假定的MOR-mGluR5异聚体远优于与受体的单价相互作用。鉴于其高效力、长作用持续时间（>24小时）和最小副作用，MMG22有潜力成为比吗啡和其他阿片类药物更优越的治疗慢性癌症疼痛的药物，并可作为一种新型药理学工具。
