In vivo Evidence for Brain Region-Specific Molecular Interactions Between Cannabinoid and Orexin Receptors.

Hye Ji J Kim,Udoka C Ezeaka,Michael J Benko,Ayat Zagzoog,Robert B Laprairie,Teagan Holt,Anna Maria Smolyakova

doi:10.3389/fnins.2021.790546

Hye Ji J Kim, Udoka C Ezeaka + Show 5 more

Open Access

https://doi.org/10.3389/fnins.2021.790546

Copy DOI

Abstract

The endocannabinoid and orexin neuromodulatory systems serve key roles in many of the same biological functions such as sleep, appetite, pain processing, and emotional behaviors related to reward. The type 1 cannabinoid receptor (CB1R) and both subtypes of the orexin receptor, orexin receptor type 1 (OX1R) and orexin receptor type 2 (OX2R) are not only expressed in the same brain regions modulating these functions, but physically interact as heterodimers in recombinant and neuronal cell cultures. In the current study, male and female C57BL/6 mice were co-treated with the cannabinoid receptor agonist CP55,940 and either the OX2R antagonist TCS-OX2-29 or the dual orexin receptor antagonist (DORA) TCS-1102. Mice were then evaluated for catalepsy, body temperature, thermal anti-nociception, and locomotion, after which their brains were collected for receptor colocalization analysis. Combined treatment with the DORA TCS-1102 and CP55,940 potentiated catalepsy more than CP55,940 alone, but this effect was not observed for changes in body temperature, nociception, locomotion, or via selective OX2R antagonism. Co-treatment with CP55,940 and TCS-1102 also led to increased CB1R-OX1R colocalization in the ventral striatum. This was not seen following co-treatment with TCS-OX2-29, nor in CB1R-OX2R colocalization. The magnitude of effects following co-treatment with CP55,940 and either the DORA or OX2R-selective antagonist was greater in males than females. These data show that CB1R-OX1R colocalization in the ventral striatum underlies cataleptic additivity between CP55,940 and the DORA TCS-1102. Moreover, cannabinoid-orexin receptor interactions are sex-specific with regards to brain region and functionality. Physical or molecular interactions between these two systems may provide valuable insight into drug-drug interactions between cannabinoid and orexin drugs for the treatment of insomnia, pain, and other disorders.

Highlights

Endocannabinoid and orexin interdependence has been a topic of growing interest in the last two decades
The OX2R antagonist TCS-OX2-29 and the Dual orexin receptor antagonists (DORA) TCS1102 were the orexin receptor compounds used in the current study
Treatment with either orexin receptor antagonist alone was associated with hypothermic, anti-nociceptive, and antilocomotive effects of smaller magnitude than that of CP55,940

Summary

Introduction

Endocannabinoid and orexin interdependence has been a topic of growing interest in the last two decades. The orexin system shares many physical and functional similarities with the ECS (Berrendero et al, 2018). It consists of the neuropeptides orexin A (OXA) and orexin B (OXB), which activate GPCRs, orexin receptor type 1 (OX1R) and type 2 (OX2R). Cannabinoid receptor (CBR) activation leads to sedative effects such as catalepsy, hypothermia, analgesia, and anti-locomotion (Metna-Laurent et al, 2017; Zagzoog et al, 2020, 2021). Orexin receptor activation increases arousal, body temperature, and modulates anti-nociception at the spinal and supraspinal levels (Yamanaka et al, 2003; Monda et al, 2005; Chiou et al, 2010). Molecular and cellular interactions between these neuromodulatory systems have physiological implications in homeostasis, neurological and psychiatric disorders, as well as in drug-drug interactions between cannabinoid and orexin drugs

Methods

Results

Conclusion