Kandasamy Ram, Hillhouse Todd M, Livingston Kathryn E, Kochan Kelsey E, Meurice Claire, Eans Shainnel O, Li Ming-Hua, White Andrew D, Roques Bernard P, McLaughlin Jay P, Ingram Susan L, Burford Neil T, Alt Andrew, Traynor John R
Edward F. Domino Research Center, Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI, 48109.
Department of Psychology, California State University, East Bay, Hayward, CA, 94542.
Proc Natl Acad Sci U S A. 2021 Apr 20;118(16). doi: 10.1073/pnas.2000017118.
Positive allosteric modulators (PAMs) of the mu-opioid receptor (MOR) have been hypothesized as potentially safer analgesics than traditional opioid drugs. This is based on the idea that PAMs will promote the action of endogenous opioid peptides while preserving their temporal and spatial release patterns and so have an improved therapeutic index. However, this hypothesis has never been tested. Here, we show that a mu-PAM, BMS-986122, enhances the ability of the endogenous opioid Methionine-enkephalin (Met-Enk) to stimulate G protein activity in mouse brain homogenates without activity on its own and to enhance G protein activation to a greater extent than β-arrestin recruitment in Chinese hamster ovary (CHO) cells expressing human mu-opioid receptors. Moreover, BMS-986122 increases the potency of Met-Enk to inhibit GABA release in the periaqueductal gray, an important site for antinociception. We describe in vivo experiments demonstrating that the mu-PAM produces antinociception in mouse models of acute noxious heat pain as well as inflammatory pain. These effects are blocked by MOR antagonists and are consistent with the hypothesis that in vivo mu-PAMs enhance the activity of endogenous opioid peptides. Because BMS-986122 does not bind to the orthosteric site and has no inherent agonist action at endogenously expressed levels of MOR, it produces a reduced level of morphine-like side effects of constipation, reward as measured by conditioned place preference, and respiratory depression. These data provide a rationale for the further exploration of the action and safety of mu-PAMs as an innovative approach to pain management.
μ-阿片受体（MOR）的正变构调节剂（PAMs）被认为可能是比传统阿片类药物更安全的镇痛药。这是基于这样一种观点，即PAMs将促进内源性阿片肽的作用，同时保留其时间和空间释放模式，因此具有更高的治疗指数。然而，这一假设从未得到验证。在此，我们表明，一种μ-PAM，BMS-986122，可增强内源性阿片肽甲硫氨酸脑啡肽（Met-Enk）在小鼠脑匀浆中刺激G蛋白活性的能力，而其自身无活性，并且在表达人μ-阿片受体的中国仓鼠卵巢（CHO）细胞中，它比β-抑制蛋白募集更能增强G蛋白激活。此外，BMS-986122增加了Met-Enk抑制中脑导水管周围灰质中GABA释放的效力，中脑导水管周围灰质是抗伤害感受的重要部位。我们描述了体内实验，证明这种μ-PAM在急性伤害性热痛和炎性疼痛的小鼠模型中产生抗伤害感受作用。这些作用被MOR拮抗剂阻断，并且与体内μ-PAMs增强内源性阿片肽活性的假设一致。由于BMS-986122不与正构位点结合，并且在内源性表达水平的MOR上没有内在激动剂作用，因此它产生的便秘、条件性位置偏爱测量的奖赏以及呼吸抑制等吗啡样副作用水平降低。这些数据为进一步探索μ-PAMs作为一种创新的疼痛管理方法的作用和安全性提供了理论依据。
