Hadjis, G. E. | Search bioRxiv

bioRxiv2026

The Endocannabinoid System's Contribution to Placebo Analgesia

Placebo analgesia--pain reduction from inert treatments--varies widely across individuals, yet its neurochemical basis remains poorly understood. While endogenous opioids, specifically {beta}-endorphin, contribute to placebo effects, mu-opioid receptor blockade does not fully abolish analgesia, implicating additional systems. Here, we investigate the endogenous cannabinoid (eCB) systems contribution to placebo analgesia in 48 healthy adults using a validated placebo paradigm with blood sampling. We quantified circulating levels of eCB ligands and {beta}-endorphin at baseline, as well as before and after placebo and control conditions to determine condition-related changes. Individual differences in placebo analgesia were associated with increases in fatty acid amide hydrolase (FAAH) substrates--a composite of anandamide, palmitoylethanolamide, and oleoylethanolamide--but not 2-arachidonoylglycerol or {beta}-endorphin alone. Critically, {beta}-endorphin moderated this relationship: FAAH substrates were strongly associated with pain reduction only when {beta}-endorphin levels were low. These findings provide evidence that eCB and opioid systems interact in a state-dependent manner during placebo analgesia in humans, with implications for understanding individual variability in treatment responses.

neuroscience↗

bioRxiv2024

Subjective salience ratings are a reliable proxy for physiological measures of arousal

Pain is an inherently salient multidimensional experience that signals potential bodily threats and promotes nocifensive behaviours. Any stimulus can be salient depending on its features and context. This poses a challenge in delineating pain-specific processes in the brain, rather than salience-driven activity. It is thus essential to salience match control (innocuous) stimuli and noxious stimuli, to remove salience effects, when aiming to delineate pain-specific mechanisms. Previous studies have salience-matched either through subjective salience ratings or the skin conductance response (SCR). The construct of salience is not intuitive, and thus matching through self-report poses challenges. SCR is used as a proxy measure that captures physiological arousal, which overcomes the nebulous construct of salience. However, SCR cannot be used to salience-match in real-time (i.e., during an experiment) and assumes an association between salience and physiological arousal elicited by painful and non-painful stimuli, but this has not been explicitly tested. To determine whether salience and physiological arousal are associated, thirty-five healthy adults experienced 30 heat pain and 30 non-painful electric stimuli of varying intensities. Stimuli were subjectively matched for salience and SCR was measured to each presentation. A linear mixed model found no differences in SCR between salience-matched heat and electric stimuli. A mediation analysis showed that salience fully mediated the relationship between stimulus intensity and SCR (proportion mediated=83%). In conclusion, salience and physiological arousal are associated, and subjective salience ratings are a suitable for salience-matching pain with non-painful stimuli. Future work can thus use subjective salience ratings to delineate pain-specific processes.

neuroscience↗