Specific changes in conduction velocity recovery cycles of single nociceptors in a patient with erythromelalgia with the I848T gain-of-function mutation of Nav1.7.

Seven patients diagnosed with erythromelalgia (EM) were investigated by microneurography to record from unmyelinated nerve fibers in the peroneal nerve. Two patients had characterized variants of sodium channel Nav1.7 (I848T, I228M), whereas no mutations of coding regions of Navs were found in 5 patients with EM. Irrespective of Nav1.7 mutations, more than 50% of the silent nociceptors in the patients with EM showed spontaneous activity. In the patient with mutation I848T, all nociceptors, but not sympathetic efferents, displayed enhanced early subnormal conduction in the velocity recovery cycles and the expected late subnormality was reversed to supranormal conduction. The larger hyperpolarizing shift of activation might explain the difference to the I228M mutation. Sympathetic fibers that lack Nav1.8 did not show supranormal conduction in the patient carrying the I848T mutation, confirming in human subjects that the presence of Nav1.8 crucially modulates conduction in cells expressing EM mutant channels. The characteristic pattern of changes in conduction velocity observed in the patient with the I848T gain-of function mutation in Nav1.7 could be explained by axonal depolarization and concomitant inactivation of Nav1.7. If this were true, activity-dependent hyperpolarization would reverse inactivation of Nav1.7 and account for the supranormal CV. This mechanism might explain normal pain thresholds under resting conditions.

Cerebral representation of the relief of itch by scratching.

Cerebral processing of itch-scratching cycles was studied with functional magnetic resonance imaging (fMRI) in healthy volunteers. The back of the hand was repetitively scratched in the absence and presence of itch induced by histamine applied close to the scratched site. Blood-oxygenation-level-dependent (BOLD) effects were assessed in predefined cortical and subcortical brain regions of interest. Scratch-related activation clusters were found in cortical and subcortical areas which had been associated before with pain processing, namely S1, S2, parietal association cortex, motor and premotor cortex, anterior and posterior insula, anterior and medial cingulum, lateral and medial frontal areas, ipsilateral cerebellum and contralateral putamen. Cortical activations were generally stronger in the contralateral hemisphere. General linear model (GLM) analysis and GLM contrast analysis revealed stronger activations during itch-related trials in the motor and premotor cortex, in lateral frontal fields of both sides, and in a left medial frontal cluster. Subcortically, stronger activation during itch-related scratching trials was found in the contralateral putamen and in the ipsilateral cerebellum. Time course analysis showed significantly higher BOLD levels during the last 3-6 s before the start of scratching when the itch intensity was strongest. This effect was found in frontal areas, in the putamen, and in the somatosensory projection areas. During the scratching, no significant differences were found between itch and control conditions with the exception of the putamen, which showed stronger activations during itch-related scratch bouts. We interpret these itch-related activations anticipating the scratching as possible cerebral correlates of the itch processing and the craving for scratch.

Translational nociceptor research as guide to human pain perceptions and pathophysiology.

Microneurography is a method for recording single unit action potentials with microelectrodes from the nerves of awake cooperating humans. Although this method is now in use since almost 40 years, its potency has been strengthened by the recent technical developments. A great progress was the discovery that different functional groups of nociceptors are characterized by a distinctly different post-excitatory slowing of their conduction velocities. Microneurography is now powerful enough to analyze the nerve activity pattern of enigmatic sensations such as pruritus. Furthermore, it is the only method providing direct insight in the changes which human nerves undergo with aging. Recently, reliable recordings from patients suffering from painful neuropathies came into reach. It has been shown that different types of neuropathies are characterized by different patterns of abnormal nociceptor functions. Although some of them are characterized by abnormal spontaneous activity in C-nociceptors, others show mainly signs of denervation. Microneurography is, therefore, a tool for translational studies on human nociceptor functions by linking direct animal studies on experimental neuropathies with human diseases.

Brain activation during input from mechanoinsensitive versus polymodal C-nociceptors.

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.

TRPA1 and TRPM8 activation in humans: effects of cinnamaldehyde and menthol.

The aim of this study was to evaluate the psychophysical effects of both TRPA1 and TRPM8 activation in humans by application of either cinnamaldehyde or menthol. We applied 10% cinnamaldehyde or 40% menthol solutions on the forearm in 10 study participants. Quantitative sensory testing and laser Doppler imaging was performed before and after exposure to the compounds. Cinnamaldehyde evoked significant spontaneous pain and induced heat and mechanical hyperalgesia, cold hypoalgesia and a neurogenic axon reflex erythema. In contrast, TRPM8 activation by menthol produced no axon reflex reaction and resulted in cold hyperalgesia. We conclude that agonists of TRPA1 and TRPM8 channels produce strikingly different psychophysical patterns.