Nociceptive sensitization and pain perception are dissociable in humans
- Matthew A. Cormie
- Pedram Mouseli
- Clizia Martini
- Kavita De Silva
- Ioana Lauric
- Omar Khalil
- David A. Seminowicz
- Massieh Moayedi
2026-08-26
Although pain and nociception are conceptually distinct, whether nociceptive sensitization can occur without pain remains unknown. Here, we show that convergent innocuous thermal stimulation elicits primary mechanical and secondary hyperalgesia without pain perception. In a preregistered study, we compared thermal grill illusion (TGI) responders (n = 96) and nonresponders (n = 64) by quantifying primary mechanical and secondary hyperalgesia following thermal grill stimulation. In responders, we further compared thermal grill-induced sensitization with that evoked by its innocuous component temperatures, noxious thermal stimuli, and expectation-matched controls. Thermal grill stimulation elicited primary mechanical and secondary hyperalgesia. Primary mechanical hyperalgesia did not differ between responders and nonresponders, whereas nonresponders exhibited greater secondary hyperalgesia. In both responders and nonresponders, sensitization exceeded an expectation threshold derived from the no-stimulation control group, indicating effects beyond those observed in the absence of thermal stimulation. Thermal grill-induced hyperalgesia was comparable to that evoked by noxious stimulation and exceeded that evoked by its innocuous component temperatures. Computational modeling in a screened sample (N = 251) revealed that pain perception, but not sensitization magnitude, was predicted by sensory, environmental, experimenter-related, and psychological factors (AUC = 0.81). These findings demonstrate that behavioral evidence consistent with nociceptive sensitization can occur independently of pain perception. This dissociation indicates that TGI responsiveness reflects a perceptual phenotype rather than sensitization itself, challenging its proposed clinical use. More broadly, these findings suggest that secondary hyperalgesia, commonly interpreted as evidence of central sensitization, can develop in the absence of pain experience, with implications for chronic pain vulnerability.