Interspecies Differences in Cannabinoid Receptor Distribution May Explain Why Animal Pain Studies Do Not Translate to Humans

CB1 and CB2 receptor expression differs substantially between species in terms of tissue distribution, cellular localization, and co-expressed markers. Pain conditions differentially alter receptor expression depending on pain type and species. These differences may explain why cannabinoid compounds that show efficacy in rodent pain models often fail in human clinical trials.

Comprehensive narrative review traversing historical and contemporary literature on cannabinoid receptor expression across the nervous system in multiple species, with focus on pain-relevant regions.

IASP recommended against cannabinoids for pain in 2021 partly due to poor clinical trial results. This review offers a mechanistic explanation: the receptors researchers target in animals may not be in the same places or on the same cells in humans.

This review reframes the cannabinoid pain debate from "do cannabinoids work?" to "are we studying them in the right model?" If receptor distributions differ between species, the entire preclinical pipeline for cannabinoid pain drugs may need redesign.

Narrative review format. Many studies used different methodologies making direct comparisons difficult. Some brain regions have limited data across species. Functional differences may not always follow expression differences.