BackgroundHuman, hairy skin contains a subgroup of C-fibers, the C-low threshold mechanoreceptive afferents ((C-LTMR) C-tactile or C-touch (CT) fibers) that are linked with the signaling of affective aspects of human touch. Recent studies suggest an involvement of these afferents in the modulation of pain in healthy volunteers. Small fiber neuropathy (SFN) is associated with a damage of C-fibers. Therefore, an impairment of C-LTMRs can be assumed. We aimed to elaborate a possible role of CT-afferents in pain modulation by investigating healthy volunteers and SFN-patients.MethodsExperiment I: 20 SFN-patients (12 women, median age 52.0 years) and 20 healthy controls (14 women, median age 43.0 years) participated in this prospective fMRI and psychophysical study. Heat-pain (HP), CT-targeted touch (slow brushing) and HP combined with CT-targeted touch were applied in randomized order to the left shank in a block design. The participants rated pain intensity on a visual analogue scale. Experiment II: We investigated a possible impact of pain intensity on CT induced pain modulation (10 healthy participants). The intensity of HP stimulation was chosen to induce pain intensity 50/100 (NRS). HP stimulation was applied with and without CT-targeted touch.ResultsExperiment I: CT-stimulation was sufficient to reduce heat pain in healthy participants (p = 0.016), but not in SFN-patients. HP induced pain intensity was significantly higher (32,2 vs 52,6) in SFN-patients. During HP, bold responses in pain associated areas were observed in both groups. Additional CT-stimulation elicited no significant difference of bold responses compared to HP. Experiment II: In healthy volunteers, we reproduced a significant reduction of HP intensity by CT-stimulation (p = 0.038).ConclusionsCT input seems to be sufficient to modulate pain, independent of intensity of the pain stimulus. As a prerequisite, the CT fibers have to be intact as in healthy volunteers. If CT fibers are impaired – as in SFN -, CT-targeted touch does not modulate pain intensity. The location of CT-induced pain modulation might be attributed to the level of the dorsal horn since the cortical activation pattern of heat pain with and without CT-targeted touch did not differ in healthy subjects and in SFN-patients.

Background Human hairy (not glabrous skin) is equipped with a subgroup of C-fibers, the C-tactile (CT) fibers. Those do not mediate pain but affective aspects of touch. CT-fiber-activation reduces experimental pain if they are intact. In this pilot study we investigated pain modulating capacities of CT-afferents in CRPS. Methods 10 CRPS-patients (mean age 33 years, SEM 3.3) and 11 healthy controls (mean age 43.2 years, SEM 3.9) participated. CT-targeted-touch (brush stroking, velocity: 3 cm/s) was applied on hairy and glabrous skin on the affected and contralateral limb. Patients rated pleasantness of CT-targeted-touch (anchors: 1 “not pleasant”—4 “very pleasant”) twice daily on 10 days. Pain intensity (NRS: 0 “no pain” – 10 “worst pain imaginable”) was assessed before, 0, 30, 60 and 120 min after each CT-stimulation. To assess sensory changes, quantitative-sensory-testing was performed at the beginning and the end of the trial period. Results CT-targeted-touch was felt more pleasant on the healthy compared to the affected limb on hairy (p < 0.001) and glabrous skin (p 0.002), independent of allodynia. In contrast to healthy controls patients felt no difference between stimulating glabrous and hairy skin on the affected limb. Thermal pain thresholds increased after CT-stimulation on the affected limb (cold-pain-threshold: p 0.016; heat-pain-threshold: p 0.033). Conclusions CT-stimulation normalizes thermal pain thresholds but has no effect on the overall pain in CRPS. Therefore, pain modulating properties of CT-fibers might be too weak to alter chronic pain in CRPS. Moreover, CT-fibers appear to lose their ability to mediate pleasant aspects of touch in CRPS.

Introduction: Small fiber neuropathies (SFN) are associated with a reduction in quality of life. In adults, epidermal nerve fiber density (END) analysis is recommended for the diagnosis of SFN. In children, END assessment is not often performed. We analyzed small nerve fiber innervation to elucidate the potential diagnostic role of skin biopsies in young patients with pain.Methods: Epidermal nerve fiber density and sudomotor neurite density (SND) were assessed in skin biopsies from 26 patients aged 7 to 20 years (15 female patients) with unexplained chronic pain. The results were compared with clinical data.Results: Epidermal nerve fiber density was abnormal in 50% and borderline in 35% of patients. An underlying medical condition was found in 42% of patients, including metabolic, autoimmune, and genetic disorders.Discussion: Reduction of epidermal nerve fibers can be associated with treatable conditions. Therefore, the analysis of END in children with pain may help to uncover a possible cause and guide potential treatment options. K E Y W O R D Sepidermal nerve fiber density, neuropathic pain, skin biopsy, small fiber, small fiber neuropathy, sudomotor neurite density, sweat gland innervation Abbreviations: AOI, area of interest; END, epidermal nerve density; NCS, nerve conduction study; PBS, phosphate-buffered saline; PGP 9.5, protein gene product 9.5; QST, quantitative sensory testing; SFN, small fiber neuropathy; SG, sweat glands; SND, sudomotor neurite density; TRP, transient receptor potential.

Objectives The thalamus plays an important role in the mediation and integration of various stimuli (e.g., somatosensory, pain, and vestibular). Whether a stimulus-specific and topographic organization of the thalamic nuclei exists is still unknown. The aim of our study was to define a functional, in vivo map of multimodal sensory processing within the human thalamus. Methods Twenty healthy individuals (10 women, 21–34 years old) participated. Defined sensory stimuli were applied to both hands (innocuous touch, mechanical pain, and heat pain) and the vestibular organ (galvanic stimulation) during 3 T functional MRI. Results Bilateral thalamic activations could be detected for touch, mechanical pain, and vestibular stimulation within the left medio-dorsal and right anterior thalamus. Heat pain did not lead to thalamic activation at all. Stimuli applied to the left body side resulted in stronger activation patterns. Comparing an early with a late stimulation interval, the mentioned activation patterns were far more pronounced within the early stimulation interval. Conclusions The right anterior and ventral-anterior nucleus and the left medio-dorsal nucleus appear to be important for the processing of multimodal sensory information. In addition, galvanic stimulation is processed more laterally compared to mechanical pain. The observed changes in activity within the thalamic nuclei depending on the stimulation interval suggest that the stimuli are processed in a thalamic network rather than a distinct nucleus. In particular, the vestibular network within the thalamus recruits bilateral nuclei, rendering the thalamus an important integrative structure for vestibular function.

The interaction between sympathetic vasoconstrictor activity to muscles [muscle sympathetic nerve activity (MSNA), burst frequency (BF) and burst incidence (BI)] and different stress and somatosensory stimuli is still unclear. Eighteen healthy men (median age 28 years) underwent microneurography recordings from the peroneal nerve. MSNA was recorded during heat pain (HP) and cold pain (CP) alone as well as combined with different stress tasks (mental arithmetic, singing, giving a speech). An additional nine healthy men (median age 26 years) underwent the stimulation protocol with an additional control task (thermal pain combined with listening to music) to evaluate possible attentional confounders. MSNA was significantly increased by CP and HP. CP-evoked responses were smaller. The diastolic blood pressure followed the time course of MSNA while heart rate remained unchanged. The mental stress tasks further increased MSNA and were sufficient to reduce pain while the control task had no effect. MSNA activity correlated negatively with pain intensity and positively with analgesia. High blood pressure values were associated with lower pain intensity. Our study indicates an impact of central sympathetic drive on pain and pain control.