Interspecies differences in the expression of cannabinoid receptors at the tissue and cellular levels

Understanding the cellular and molecular distribution of cannabinoids can address a highly contentious perspective in the pain neuroscience field: whether cannabinoids are viable in pain relief. Due to insufficient evidence for cannabinoids in reducing pain in clinical trials and gaps in knowledge across the translational research process, the International Association for the Study of Pain (IASP) published a position statement in 2021 recommending against the general use of cannabinoids to treat pain. A possible mechanistic reason for the lack of translatability is interspecies differences in the expression of the cannabinoid type 1 and type 2 receptors at the tissue and cellular levels. Additionally, the anatomical site that is most important for analgesia has been elusive. This review aims to provide a deeper understanding of the anatomical distribution of cannabinoid receptors throughout the nervous system across species. We traverse historical and contemporary literature to illustrate the progression of methodology and perspectives. We discuss co-localized markers on cannabinoid receptor-expressing cells to elucidate possible anatomically dependent roles of the endocannabinoid system. We also discuss differences in cannabinoid receptor expression across species that may contribute to challenges in translatability between rodents and humans. Lastly, we cover how various types of pain can differentially alter the expression of cannabinoid receptors and how this may impact cannabinoid-based therapeutics.