Involvement of the orexin/hypocretin system in the pharmacological effects induced by Δ ⁹‐tetrahydrocannabinol

Abstract

Background and Purpose

Anatomical, biochemical and pharmacological evidence suggest the existence of a crosstalk between the orexinergic and endocannabinoid systems. While the orexin receptor 1 (OX ₁ receptor) modulates the reinforcing properties of cannabinoids, the participation of orexins in the acute pharmacological effects of Δ ⁹‐tetrahydrocannabinol (THC) remains unexplored.

Experimental Approach

We assessed the possible role of orexins in THC‐induced hypolocomotion, hypothermia, antinociception, anxiolytic‐ and anxiogenic‐like effects and memory impairment. Selective OX ₁ and OX ₂ receptor antagonists and OX ₁ knockout (KO) mice as well as prepro‐orexin (PPO) KO mice were used as pharmacological and genetic approaches. CB ₁ receptor levels in control and PPO KO mice were evaluated by immunoblot analysis. The expression of c‐Fos after THC treatment was analysed in several brain areas in wild‐type mice and in mice lacking the PPO gene.

Key Results

The hypothermia, supraspinal antinociception and anxiolytic‐like effects induced by THC were modulated by orexins through OX ₂ receptor signalling. OX ₁ receptors did not seem to be involved in these THC responses. No differences in CB ₁ receptor levels were found between wild‐type and PPO KO mice. THC‐induced increase in c‐Fos expression was reduced in the central amygdala, medial preoptic area and lateral septum in these mutant mice.

Conclusions and Implications

Our results provide new findings to further clarify the interaction between orexins and cannabinoids. OX ₁ and OX ₂ receptors are differently implicated in the pharmacological effects of cannabinoids.