Background & Aims
Understanding the neural mechanisms that subserve placebo analgesia and nocebo hyperalgesia would allow for the development of novel treatments for pain conditions that exploit and inhibit these phenomena, respectively. Rodent models of placebo analgesia and nocebo hyperalgesia are essential for investigations at the cellular and subcellar levels. Indeed, with the use of the wide range of genetic tools, studies have begun to identify specific brain regions, neurotransmitters, and circuits that appear to be critical for producing these effects (e.g., Xu et al., 2018, Chen et al., 2024). Underlying the use of rodent models is an assumption that rodents and humans utilize similar or homologous neural circuits when mounting these responses. However, no efforts have yet been made to check this assumption. As such, this study directly compares the regional neural activity and functional connectivity associated with both placebo analgesia and nocebo hyperalgesia between humans and rats.
Methods
Both humans and rats underwent a response-conditioning procedure to elicit either placebo analgesia or nocebo hyperalgesia. Contextual cues were repeatedly paired with either high pain (nocebo), low pain (placebo) or moderate pain (control). Following this, the moderate stimulus was delivered in the presence of these contextual cues and decreases and increases in pain compared to control indicated placebo analgesia or nocebo hyperalgesia. Brain activity during these responses was quantified in humans (fMRI) and rats (c-Fos expression) in 70 homologous brain regions known to be involved in the processing of pain and contextual cues. Regional activity changes (relative to control) and functional connectivity of these 70 regions was calculated for both placebo and nocebo. To compare regional activity between species, the top 20 brain regions that showed the largest changes were identified, while for functional connectivity the top 100 connections of humans and rats were compared.
Results
The response conditioning procedure elicited strong placebo analgesia and nocebo hyperalgesia in subpopulations of both humans and rats. For placebo analgesia, 5 brain regions were identified in the top 20 for both humans and rats. These were the paraventricular thalamus, the septal nuclei, the basolateral amygdala, the medial parabrachial nucleus and the gracile/cuneate nucleus. For nocebo hyperalgesia, 7 brain regions were identified in the top 20 for both humans and rats. These were the orbitofrontal cortex, the paraventricular hypothalamus, the medial and lateral parabrachial nuclei, the locus coeruleus, the rostral ventromedial medulla, and the gracile/cuneate nuclei. For the functional connectivity, 26 ROI-ROI shared connections were identified in both humans and rats during placebo analgesia, while 12 were found during nocebo hyperalgesia.
Conclusions
This is the first study to directly compare the regional activity and functional circuitry underlying placebo analgesia and nocebo hyperalgesia in both humans and rats. The results suggests that there is significant cross-species overlap in the brain regions and functional circuits that are activated during these responses. This indicates that the neural mechanisms that subserve placebo analgesia and nocebo hyperalgesia appear to be at least partly conserved across species. By targeting these conserved regions and circuits identified in this study, researchers using rodent models of placebo and nocebo can now take a more focused approach to ensure that their studies will have the best chance for translational relevance.
References
Xu, L, Wan, Y, Ma, L, Zheng, J, Han, B, Liu, FY, Yi, M & Wan, Y (2018), ‘A Context-Based Analgesia Model in Rats: Involvement of Prefrontal Cortex’, Neurosci Bull, vol. 34, no. 6, pp. 1047-1057.
Chen, B, Goldstein, N, Dziubek, J, Zhao, S, Harrahill, A, Sundai, A, Choi, S, Prevosto, V, Wang, F (2024), ‘Reverse Engineering Placebo Analgesia’, bioRxiv 2024.02.12.579946; doi: https://doi.org/10.1101/2024.02.12.579946
Presenting Author
Damien Boorman
Poster Authors
Topics
- Placebo