Cátedra de Fisiología, Facultad de Odontología, Universidad de Buenos Aires, Argentina; Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Argentina.
Centro de Estudios Farmacológicos y Botánicos, CEFyBO-CONICET-UBA, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina.
Psychoneuroendocrinology. 2018 Jan;87:131-140. doi: 10.1016/j.psyneuen.2017.10.015. Epub 2017 Oct 18.
Activation of the hypothalamic-pituitary-adrenal axis (HPA) is critical for survival when the organism is exposed to a stressful stimulus. The endocannabinoid system (ECS) is currently considered an important neuromodulator involved in numerous pathophysiological processes and whose primary function is to maintain homeostasis. In the tissues constituting the HPA axis, all the components of the ECS are present and the activation of this system acts in parallel with changes in the activity of numerous neurotransmitters, including nitric oxide (NO). NO is widely distributed in the brain and adrenal glands and recent studies have shown that free radicals, and in particular NO, may play a crucial role in the regulation of stress response. Our objective was to determine the participation of the endocannabinoid and NOergic systems as probable mediators of the neuroendocrine HPA axis response to a psychophysical acute stress model in the adult male rat. Animals were pre-treated with cannabinoid receptors agonists and antagonists at central and systemic level prior to acute restraint exposure. We also performed in vitro studies incubating adrenal glands in the presence of ACTH and pharmacological compounds that modifies ECS components. Our results showed that the increase in corticosterone observed after acute restraint stress is blocked by anandamide administered at both central and peripheral level. At hypothalamic level both cannabinoid receptors (CB1 and CB2) are involved, while in the adrenal gland, anandamide has a very potent effect in suppressing ACTH-induced corticosterone release that is mainly mediated by vanilloid TRPV1 receptors. We also observed that stress significantly increased hypothalamic mRNA levels of CB1 as well as adrenal mRNA levels of TRPV1 receptor. In addition, anandamide reduced the activity of the nitric oxide synthase enzyme during stress, indicating that the anti-stress action of endocannabinoids may involve a reduction in NO production at hypothalamic and adrenal levels. In conclusion, an endogenous cannabinoid tone maintains the HPA axis in a stable basal state, which is lost with a noxious stimulus. In this case, the ECS dampens the response to stress allowing the recovery of homeostasis. Moreover, our work further contributes to in vitro evidence for a participation of the endocannabinoid system by inhibiting corticosterone release directly at the adrenal gland level.
下丘脑-垂体-肾上腺轴 (HPA) 的激活对于机体暴露于应激刺激时的生存至关重要。内源性大麻素系统 (ECS) 目前被认为是一种重要的神经调节剂，参与许多病理生理过程，其主要功能是维持内稳态。在构成 HPA 轴的组织中，ECS 的所有成分都存在，并且该系统的激活与许多神经递质活性的变化平行，包括一氧化氮 (NO)。NO 广泛分布于大脑和肾上腺，最近的研究表明，自由基，特别是 NO，可能在调节应激反应中发挥关键作用。我们的目的是确定内源性大麻素和 NO 能系统作为成年雄性大鼠神经内分泌 HPA 轴对心理物理急性应激模型反应的可能介导物的参与。动物在急性束缚暴露前预先用大麻素受体激动剂和拮抗剂进行中枢和全身预处理。我们还进行了体外研究，在存在 ACTH 和改变 ECS 成分的药理学化合物的情况下孵育肾上腺。我们的结果表明，急性束缚应激后观察到的皮质酮增加被同时在中枢和外周给予的大麻素类似物阻断。在下丘脑水平，两种大麻素受体 (CB1 和 CB2) 都参与其中，而在肾上腺中，大麻素类似物在抑制 ACTH 诱导的皮质酮释放方面具有非常强的作用，主要由香草素 TRPV1 受体介导。我们还观察到应激显著增加了下丘脑 CB1 的 mRNA 水平以及肾上腺 TRPV1 受体的 mRNA 水平。此外，在应激期间，大麻素类似物降低了一氧化氮合酶酶的活性，表明内源性大麻素的抗应激作用可能涉及减少下丘脑和肾上腺水平的 NO 产生。总之，内源性大麻素张力使 HPA 轴保持在稳定的基础状态，而有害刺激会使其丧失。在这种情况下，ECS 抑制应激反应，允许内稳态的恢复。此外，我们的工作通过直接在肾上腺水平抑制皮质酮释放，进一步为内源性大麻素系统参与提供了体外证据。
