Department of Anesthesiology, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY, 11794, USA.
Stony Brook University Pain and Analgesia Research Center (SPARC), Renaissance School of Medicine, Stony Brook University, Stony Brook, NY, 11794, USA.
Sci Rep. 2022 Jun 2;12(1):9241. doi: 10.1038/s41598-022-13284-0.
The endocannabinoid anandamide (AEA) produces antinociceptive effects by activating cannabinoid receptor 1 (CB1). However, AEA also serves as an agonist at transient receptor potential vanilloid receptor 1 (TRPV1) in nociceptive sensory neurons, which may exacerbate pain. This potential functional duality is highlighted by the failure of an inhibitor of the AEA catabolic enzyme fatty acid amide hydrolase (FAAH) to afford pain relief in a clinical trial. Consequently, it remains to be determined whether elevating AEA levels in nociceptors leads to antinociceptive or pro-nociceptive effects. Fatty acid binding protein 5 (FABP5) is an intracellular carrier that mediates AEA transport to FAAH for inactivation. Leveraging the abundant expression of FABP5 in TRPV1 nociceptors, we employed a conditional knockout strategy to demonstrate that FABP5 deletion in nociceptors augments AEA levels, resulting in the emergence of antinociceptive effects mediated by CB1. Mechanistically, FABP5 deletion suppresses inflammation- and nerve growth factor-mediated TRPV1 sensitization via CB1, an effect mediated by calcineurin. Unexpectedly, inhibition of FAAH failed to blunt TRPV1 sensitization, uncovering functionally distinct outputs resulting from FABP5 and FAAH inhibition. Collectively, our results demonstrate that FABP5 serves a key role in governing endocannabinoid signaling in nociceptors to disrupt TRPV1 sensitization and pain, and position FABP5 as a therapeutic target for the development of analgesics.
内源性大麻素大麻素（AEA）通过激活大麻素受体 1（CB1）产生镇痛作用。然而，AEA 也作为瞬时受体电位香草素受体 1（TRPV1）在伤害感受神经元中的激动剂，这可能会加剧疼痛。这种潜在的功能双重性突出表现在脂肪酸酰胺水解酶（FAAH）的 AEA 代谢酶抑制剂在临床试验中未能提供缓解疼痛的效果。因此，仍然需要确定在伤害感受器中升高 AEA 水平是否会导致镇痛或促伤害感受效应。脂肪酸结合蛋白 5（FABP5）是一种细胞内载体，介导 AEA 向 FAAH 的运输以使其失活。利用 FABP5 在 TRPV1 伤害感受器中的丰富表达，我们采用条件性敲除策略证明，伤害感受器中 FABP5 的缺失会增加 AEA 水平，从而产生由 CB1 介导的镇痛作用。从机制上讲，FABP5 的缺失通过 CB1 抑制炎症和神经生长因子介导的 TRPV1 敏化，这是一种由钙调神经磷酸酶介导的作用。出乎意料的是，抑制 FAAH 未能阻止 TRPV1 敏化，揭示了源自 FABP5 和 FAAH 抑制的功能不同的输出。总之，我们的研究结果表明，FABP5 在调节伤害感受器中的内源性大麻素信号中起着关键作用，以破坏 TRPV1 敏化和疼痛，并将 FABP5 定位为开发镇痛药的治疗靶点。
