Placebo analgesia and nocebo hyperalgesia across species: direct neural comparisons between rats and humans

Placebo analgesia and nocebo hyperalgesia can profoundly alter pain perception, offering critical implications for pain management. While animal models are increasingly used to explore the underlying mechanisms of these phenomena, it remains unclear whether animals experience placebo and nocebo effects in a manner comparable to humans or whether the associated neurobiological pathways are conserved across species. In this study, we introduce a novel framework for comparing brain activity between humans and rodents during placebo analgesia and nocebo hyperalgesia. Using c-Fos immunohistochemistry in rats and fMRI in humans, we examined neural activity in 70 pain-related brain regions, identifying both species-specific and conserved connectivity changes. Functional connectivity analysis, refined by pruning connections based on anatomical pathways, revealed significant overlap in key regions, including the amygdala, anterior cingulate cortex, and nucleus accumbens, highlighting conserved circuits driving placebo and nocebo responses This cross-species methodology offers a powerful new approach for investigating the neurobiology of pain modulation, bridging the gap between animal models and human studies. Identifying these common connections validates the use of animal models and enables preclinical researchers to focus on circuits that are conserved across species, ensuring greater translational relevance when developing new and effective treatments for pain conditions.