Down-regulation of NR2B receptors contributes to the analgesic and antianxiety effects of enriched environment mediated by endocannabinoid system in the inflammatory pain mice

Chronic pain states are highly prevalent and yet poorly controlled by currently available analgesics. It has been reported that enriched environment (EE), as a new way of endogenous pharmacotherapy, is effective in attenuating chronic inflammatory pain. However, the underlying molecular mechanisms are still not fully understood. NMDA NR2B receptor plays a critical role in pain transmission and modulation. Thus, in this study, we aimed at the effect of EE on the NR2B receptors expression in the prefrontal cortex, hippocampus and thalamus in the inflammatory pain mice. The results showed a significant increase of NR2B receptors in the thalamus of mice at 7 d following injection of CFA in the subcutaneous of the bottom of the left hind paw. EE significantly reduced the duration of mechanical hypersensitivity and anxiety-related behavior and the expression of NR2B receptors as compared to the standard condition. Furthermore, EE significantly increased 2-arachidonoylglycero (2-AG) levels at 7 d in the inflammatory pain mice as compared to the standard condition, and the effect of EE on the behavior and the expression of NR2B receptors was abolished by intraperitoneal injection of AM281 (a selective antagonist of CB1 receptor). Elevated 2-AG levels by intraperitoneal injection of JZL184 (a selective inhibitor of MAGL, the enzyme responsible for 2-AG hydrolysis) produced the same effect as EE. Results from this study provide the evidence that EE mimics endocannabinoids to take analgesic and anti-anxiety activities by decreasing the expression of the NR2B receptors via the CB1 receptor in the thalamus, pending further studies.

Automated summary

This study examined the effects of enriched environment (EE) on the expression of NR2B receptors in mice with inflammatory pain. The results showed that EE significantly reduced mechanical hypersensitivity and anxiety-related behavior, and decreased the expression of NR2B receptors. Additionally, EE increased the levels of 2-arachidonoylglycero (2-AG, an endocannabinoid) in the mice. The analgesic and anti-anxiety effects of EE were mediated by the CB1 receptor, and could be replicated by elevating 2-AG levels with a selective inhibitor of MAGL.