ABSTRACT
C-nociceptors mediating cutaneous pain in humans can be distinguished in mechano-heat-responsive units (CMH) and mechano-insensitive units (CMi). However, if sensitized in damaged tissue, CMi play an important role in inflammatory pain. CMi differ from CMH by higher electrical thresholds and by mediating the axon reflex. Using these properties, we established two stimulation paradigms: (1) transcutaneous stimulation (TCS) of low current density below the CMi threshold and (2) intracutaneous stimulation (ICS) of high current density that excites CMi. This was proven by the quantification of the axon-reflex flare. Applying these stimulation paradigms during functional magnetic resonance imaging, we investigated whether nociceptor stimulation that recruits CMi leads to different cerebral activation than stimuli that do not recruit CMi. Brain activation by CMi was inferred by subtraction. Both stimuli recruited multiple afferents other than CMi, and we expected a common network of regions involved in different aspects of pain perception and motor nocifensive reactions in both stimuli. ICS that additionally recruited CMi should activate regions with low acuity that are involved in pain memory and emotional attribution. Besides a common network of pain in both stimuli, TCS activated the supplementary motor area, motor thalamic nuclei, the ipsilateral insula, and the medial cingulate cortex. These regions contribute to a pain processing loop that coordinates the nocifensive motor reaction. CMi nociceptor activation did not cause relevant activation in this loop and does not seem to play a role in withdrawal. The posterior cingulate cortex was selectively activated by ICS and is apparently important for the processing of inflammatory pain.
