A review of cannabinoid receptor expression across species reveals significant differences between rodents and humans in receptor distribution, cell-type localization, and pain-induced changes, which may explain the poor translation of cannabinoid pain research from animals to clinical trials.
Pain researchers, pharmaceutical developers targeting cannabinoid receptors, and translational neuroscientists.
IASP recommended against cannabinoids for pain due to poor clinical evidence
What the researchers found
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.
Why it matters
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.
The numbers in context
IASP 2021 position statement against cannabinoids for pain. Review covers CB1 and CB2 distribution across CNS, PNS, and immune cells in rodents, primates, and humans.
How the study worked
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.
What this study cannot tell us
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.
How to read the evidence
Comprehensive cross-species comparison with important translational implications, but narrative format and reliance on heterogeneous methodologies limit certainty.
When this study was published
2025 review addressing a critical gap in cannabinoid pain research translation.
The bigger picture
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.
Questions still open
- Should cannabinoid pain research pivot to human-tissue-based models?
- Which anatomical site is most important for cannabinoid analgesia in humans?
Common questions
Why do cannabinoids work for pain in mice but not in humans?
Should cannabinoids be used for pain?
Read the original research
Interspecies differences in the expression of cannabinoid receptors at the tissue and cellular levels.
Neural regeneration research
Citation
Lawley, Sydney; Green, Audrey; Johnson, Cole; Burton, Michael D. (2025). Interspecies differences in the expression of cannabinoid receptors at the tissue and cellular levels.. Neural regeneration research. https://doi.org/10.4103/NRR.NRR-D-25-00806
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