Department of Pharmacology, Biological Sciences Building, Federal University of Paraná, Rua Coronel H. dos Santos S/N, P.O. Box 19031, Curitiba, Paraná 81540-990, Brazil.
Department of Pharmacology, School of Medicine, University of São Paulo, Av. Bandeirantes 3900, Ribeirão Preto, São Paulo 14049-900, Brazil.
Pharmacol Biochem Behav. 2020 Jul;194:172938. doi: 10.1016/j.pbb.2020.172938. Epub 2020 May 3.
Evidence indicates that periaqueductal gray matter (PAG) plays an important role in defensive responses and pain control. The activation of cannabinoid type-1 (CB1) or mu-opioid (MOR) receptors in the dorsal region of this structure (dPAG) inhibits fear and facilitates antinociception induced by different aversive stimuli. However, it is still unknown whether these two receptors work cooperatively in order to achieve these inhibitory actions. This study investigated the involvement and a likely interplay between CB1 and MOR receptors localized into the dPAG on the regulation of fear-like defensive responses and antinociception (evaluated in tail-flick test) evoked by dPAG chemical stimulation with N-methyl-d-aspartate (NMDA). Before the administration of NMDA, animals were first intra-dPAG injected with the CB1 agonist ACEA (0.5 pmol), or with the MOR agonist DAMGO (0.5 pmol) in combination with the respective antagonists AM251 (CB1 antagonist, 100 pmol) or CTOP (MOR antagonist, 1 nmol). To investigate the interplay between these receptors, microinjection of CTOP was combined with ACEA, or microinjection of AM251 was combined with DAMGO. Our results showed that both the intra-PAG treatments with ACEA or DAMGO inhibited NMDA-induced freezing expression, whereas only the treatment with DAMGO increased antinociception induced with NMDA, which are completely blocked by its respective antagonists. Interestingly, the inhibitory effects of ACEA or DAMGO on freezing was blocked by CTOP and AM251, respectively, indicating a functional interaction between these two receptors in the mediation of defensive behaviors. However, this cooperative interaction was not observed during the NMDA-induced antinociception. Our findings indicate that there is a cooperative action between the MOR and CB1 receptors within the dPAG and it is involved in the mediation of NMDA-induced defensive responses. Additionally, the MORs into the dPAG are involved in the modulation of the antinociceptive effects that follow a fear-like defense-reaction induced by dPAG chemical stimulation with NMDA.
证据表明，导水管周围灰质（periaqueductal gray matter，PAG）在防御反应和疼痛控制中发挥着重要作用。在该结构的背侧区域（dPAG）激活大麻素 1 型（cannabinoid type-1，CB1）或μ-阿片（mu-opioid，MOR）受体可抑制恐惧，并促进不同厌恶刺激诱导的抗伤害作用。然而，目前尚不清楚这两种受体是否协同作用以产生这些抑制作用。本研究旨在探讨 dPAG 中的 CB1 和 MOR 受体在调节由 dPAG 内 NMDA 化学刺激引起的防御性反应和抗伤害作用（通过尾部闪烁测试评估）中的作用及其可能的相互作用。在 NMDA 给药之前，动物首先在 dPAG 内注射 CB1 激动剂 ACEA（0.5 pmol），或在 dPAG 内注射 MOR 激动剂 DAMGO（0.5 pmol），同时注射各自的拮抗剂 AM251（CB1 拮抗剂，100 pmol）或 CTOP（MOR 拮抗剂，1 nmol）。为了研究这些受体之间的相互作用，将 CTOP 与 ACEA 联合微注射，或 AM251 与 DAMGO 联合微注射。结果表明，dPAG 内注射 ACEA 或 DAMGO 均可抑制 NMDA 诱导的冻结表达，而只有 DAMGO 处理可增加 NMDA 诱导的抗伤害作用，而这两种作用均被各自的拮抗剂完全阻断。有趣的是，ACEA 或 DAMGO 对冻结的抑制作用被 CTOP 和 AM251 分别阻断，表明这两种受体在防御行为的介导中存在功能相互作用。然而，在 NMDA 诱导的抗伤害作用中没有观察到这种协同作用。我们的研究结果表明，dPAG 内 MOR 和 CB1 受体之间存在协同作用，该作用参与了 NMDA 诱导的防御反应的介导。此外，dPAG 中的 MOR 参与调节由 NMDA 诱导的防御反应引起的、dPAG 内 NMDA 化学刺激后产生的抗伤害作用。
