Regulatory role of the cannabinoid CB₂ receptor in stress‐induced neuroinflammation in mice

Background and Purpose

Stress exposure produces excitotoxicity and neuroinflammation, contributing to the cellular damage observed in stress‐related neuropathologies. The endocannabinoids provide a homeostatic system, present in stress‐responsive neural circuits. Here, we have assessed the possible regulatory role of cannabinoid CB₂ receptors in stress‐induced excitotoxicity and neuroinflammation.

Experimental Approach

We used wild type (WT), transgenic overexpressing CB₂ receptors (CB2xP) and CB₂ receptor knockout (CB2‐KO) mice exposed to immobilization and acoustic stress (2 h·day⁻¹ for 4 days). The CB₂ receptor agonist JWH‐133 was administered daily (2 mg·kg⁻¹, i.p.) to WT and CB2‐KO animals. Glutamate uptake was measured in synaptosomes from frontal cortex; Western blots and RT‐PCR were used to measure proinflammatory cytokines, enzymes and mediators in homogenates of frontal cortex.

Key Results

Increased plasma corticosterone induced by stress was not modified by manipulating CB₂ receptors. JWH‐133 treatment or overexpression of CB₂ receptors increased control levels of glutamate uptake, which were reduced by stress back to control levels. JWH‐133 prevented the stress‐induced increase in proinflammatory cytokines (TNF‐α and CCL2), in NF‐κB, and in NOS‐2 and COX‐2 and in the consequent cellular oxidative and nitrosative damage (lipid peroxidation). CB2xP mice exhibited anti‐inflammatory or neuroprotective actions similar to those in JWH‐133 pretreated animals. Conversely, lack of CB₂ receptors (CB2‐KO mice) exacerbated stress‐induced neuroinflammatory responses and confirmed that effects of JWH‐133 were mediated through CB₂ receptors.

Conclusions and Implications

Pharmacological manipulation of CB₂ receptors is a potential therapeutic strategy for the treatment of stress‐related pathologies with a neuroinflammatory component, such as depression.

DOI: 10.1111/bph.12607

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