Reply to Zhuang et al.: Potential side effects of positive allosteric modulators of the mu-opioid receptor.
Reply to Zhuang et al.: Potential side effects of positive allosteric modulators of the mu-opioid receptor.
复制标题
回复 Zhuang 等人：mu-阿片受体正变构调节剂的潜在副作用。
DOI：
10.1073/pnas.2108493118
复制
发表时间：
2021
影响因子：
11.1
通讯作者：
Traynor,JohnR
中科院分区：
文献类型：
--
作者：
Traynor,JohnR
我很欣赏Zhuang等人最近的评论。(1)在我们的报告上。我们工作的目的（2）是建立概念证据，即μ-阿片受体（莫尔）的正变构调节剂（PAM）通过增强作用于莫尔的阿片肽的活性在小鼠中提供抗伤害感受。为了使PAM具有活性，需要释放内源性阿片肽。我们还表明，在幼稚动物中，PAM不会引起便秘或条件性位置偏爱，表明缺乏奖励特性，并且与同等剂量的吗啡相比，仅最低限度地抑制呼吸。Zhuang等人指出，由于疼痛的感觉和情绪方面之间的关系，需要研究PAM在病理性疼痛模型中的副作用特征（1）。我们完全同意这一建议;事实上，我们在我们的论文中报告的PAM的小的致炎作用是纳洛酮可逆的，表明释放的内源性阿片类药物的作用。因此，我们在论文中得出结论，早期临床前数据足以推动进一步评估副作用。很少有研究评估新型阿片类药物对慢性疼痛受试者的奖励作用或其他副作用。然而，我们同意，根据莫尔PAM的作用方式，这一点很重要。这些研究正在进行中，我们乐观地认为，肽在大脑区域的差异性空间和时间释放将为PAM提供选择性作用，这仅在莫尔的正构位点被占据时有效（3）。此外，脑啡肽酶抑制剂引起的阿片肽水平的全球增加并不产生
I appreciate the recent comments by Zhuang et al.(1) on our report. The aim of our work (2) was to establish proof of concept that a positive allosteric modulator (PAM) of the mu-opioid receptor (MOR) affords antinociception in mice by amplifying the activity of opioid peptides acting at MOR. For the PAM to be active, endogenous opioid peptide release is required. We also show that in naive animals the PAM does not cause constipation or a conditioned place preference, indicating a lack of rewarding properties, and only inhibits respiration minimally compared to an equivalent dose of morphine.In their letter, Zhuang et al. point out the need to investigate the side-effect profile of the PAM in pathological pain models because of the relationship between the sensory and emotional aspects of pain (1). We fully concur with this suggestion; indeed, the small respiratory-depressant effect of the PAM we report in our paper is naloxone-reversible, suggesting a role for released endogenous opioids. Consequently, we conclude in the paper that the early preclinical data are promising enough to move forward with further evaluation of side effects. Few studies evaluate the rewarding effects or other side effects of novel opioids in subjects experiencing chronic pain. However, we agree that this is important based on the mode of action of the MOR PAM. Such studies are ongoing and we are optimistic that the differential spatial and temporal release of peptides across brain regions will provide selectivity of action for the PAM, which is only effective when the orthosteric site of MOR is occupied (3). In addition, the global increase in opioid peptide levels with enkephalinase inhibitors does not produce