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.

有证据表明，导水管周围灰质（PAG）在防御反应和疼痛控制中起着重要作用。该结构背侧区域（dPAG）中的1型大麻素（CB1）或mu阿片类药物（MOR）受体的激活抑制恐惧并促进由不同厌恶刺激引起的抗伤害感受。然而，仍然不清楚这两种受体是否协同起作用以实现这些抑制作用。这项研究调查了dPAG中CB1和MOR受体之间的参与以及可能的相互作用，这些作用是通过dPAG化学刺激与N-甲基-d诱发的恐惧样防御反应和抗伤害感受的调节（在甩尾试验中评估）。-天冬氨酸（NMDA）。在施用NMDA之前，首先在dPAG内向动物注射CB1激动剂ACEA（0.5 pmol）或MOR激动剂DAMGO（0.5 pmol）与相应的拮抗剂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显微注射与ACEA组合，或将AM251显微注射与DAMGO组合。我们的结果表明，ACEA或DAMGO的PAG内治疗均抑制NMDA诱导的冰冻表达，而只有DAMGO的处理增加了NMDA诱导的抗伤害感受，这被其各自的拮抗剂完全阻断。有趣的是，ACEA或DAMGO对冷冻的抑制作用分别被CTOP和AM251阻断，表明这两个受体之间在防御行为的介导中的功能相互作用。但是，在NMDA诱导的抗伤害感受过程中未观察到这种协同作用。我们的发现表明，dPAG中的MOR和CB1受体之间存在协同作用，并且它参与NMDA诱导的防御反应的介导。此外，进入dPAG的MORs参与了抗伤害感受作用的调节，该作用是由NMDA的dPAG化学刺激诱导的恐惧样防御反应之后产生的。我们的发现表明，dPAG中的MOR和CB1受体之间存在协同作用，并且它参与NMDA诱导的防御反应的介导。此外，进入dPAG的MORs参与了抗伤害感受作用的调节，该作用是由NMDA的dPAG化学刺激诱导的恐惧样防御反应之后产生的。我们的发现表明，dPAG中的MOR和CB1受体之间存在协同作用，并且它参与NMDA诱导的防御反应的介导。另外，进入dPAG的MOR参与了抗伤害感受作用的调节，该作用是由NMDA的dPAG化学刺激诱导的恐惧样防御反应。