Peripheral Nociceptor Activity and Placebo Hypoalgesia: A Proof-of-Concept Study

Placebo effects illustrate clearly how cognitive states can influence physiological processes. While central mechanisms of placebo hypoalgesia, i.e. reduce sensitivity to painful stimuli due to expectations, are well established, it remains unclear whether such expectations modulate also peripheral activity. In this proof-of-principle study, we combined a well-established placebo paradigm with microneurography to directly assess responses of single nerve fibers in awake humans. Six healthy participants (18 fibers) underwent each a placebo and a control condition in a randomized crossover design. Placebo hypoalgesia was induced using verbal suggestion and classical conditioning. Manipulation checks confirmed that participants expected hypoalgesic effects of a placebo gel after conditioning. At the peripheral level, data on the recovery cycle of the nerve fibers indicated changes in the excitability of sleeping nociceptors (CMi) in the placebo compared to control condition, namely with enhanced and longer-lasting early subnormality. While other microneurographic outcome measures showed no consistent placebo effects, rather strong time-dependent reductions in fiber responsiveness independent of the experimental conditions were observed. These findings provide preliminary evidence that modulation of peripheral nociceptor activity by cognitive states, specifically expectations, is possible. Such modulation of peripheral activity appears to be fiber-type specific. Time effects have been neglected in microneurographic protocols. The pronounced time effects found here highlight the need for optimized such protocols.