Human Studies

The canonical view is that touch is signaled by fast-conducting, thickly myelinated afferents, whereas pain is signaled by slow-conducting, thinly myelinated ("fast" pain) or unmyelinated ("slow" pain) afferents. While other mammals have thickly myelinated afferents signaling pain (ultrafast nociceptors), these have not been demonstrated in humans. Here, we performed single-unit axonal recordings (microneurography) from cutaneous mechanoreceptive afferents in healthy participants. We identified A-fiber high-threshold mechanoreceptors (A-HTMRs) that were insensitive to gentle touch, encoded noxious skin indentations, and displayed conduction velocities similar to A-fiber low-threshold mechanoreceptors. Intraneural electrical stimulation of single ultrafast A-HTMRs evoked painful percepts. Testing in patients with selective deafferentation revealed impaired pain judgments to graded mechanical stimuli only when thickly myelinated fibers were absent. This function was preserved in patients with a loss-of-function mutation in mechanotransduction channel PIEZO2. These findings demonstrate that human mechanical pain does not require PIEZO2 and can be signaled by fast-conducting, thickly myelinated afferents.

Features of the pain in hypermobile Ehlers-Danlos syndrome (hEDS) are complex and insufficiently known by clinicians. We enrolled 37 hEDS patients. Disease status was ascertained using revised 2017 International Classification criteria, in the EDS French National Reference Center. Patients were evaluated with a clinical examination, quantitative sensory testing, and validated questionnaires. Thirty-seven patients were evaluated. Pain had appeared at 10 ± 5 years old and became chronic at 20 ± 9 years old. hEDS was diagnosed at only 24 ± 10 years old. Ninety-seven percent of them had severe chronic pain, which gradually increased over time in 75% of them. The main location of pain was in joints and predominated in lower limbs. Patients with a generalized presentation of pain had older chronic pain and a higher impact on the affective component. Neuropathic pain was frequent in the most painful joint and associated with heat hypoesthesia. An asymmetric proprioception was found in one third of the patients. A very high rate of attempted suicide was observed. To conclude, pain in hEDS is severe, chronic, and disabling. Sensorial and proprioceptive sensibilities are also affected. Peripheral neuropathic pain is frequent and central sensitization appears to be a key step in the evolution of disease.

Multimodal neuroimaging studies provide support for a role of alterations in sensory processing circuits and endogenous pain modulatory systems in provoked vestibulodynia (PVD). In this study we tested the hypotheses that PVD compared to healthy controls (HCs) would demonstrate gray matter volume (GMV) alterations in regions associated with sensorimotor, corticothalamic, and basal ganglia circuits. We also tested the replicability of previously reported gray matter increases in basal ganglia and hippocampal volumes in PVD versus HCs. Additionally, disease-specificity of GMV alterations were examined by comparing PVD to another chronic pain disorder. Finally we examine whether GMV alterations are correlated with symptom measures. Structural magnetic resonance imaging was obtained in 119 premenopausal women (45 PVD, 45 HCs, 29 irritable bowel syndrome (IBS)). A voxel-based morphometry analysis was applied to determine group differences in the hypothesized regions of interest. Compared to HCs, PVD women exhibited greater GMV in the basal ganglia, hippocampus, and sensorimotor cortices. Compared to IBS patients, women with PVD had greater GMV in the hippocampus, and sensorimotor network, but lower GMV in the thalamus and precentral gyrus. Regional gray matter volume alterations were associated with patient reports of pain during intercourse and muscles tenderness. The current findings provide further evidence that GMV is increased in PVD compared to HCs in several regions of the sensorimotor network and the hippocampus in PVD patients. In addition, GMV distinct alterations in the sensorimotor network were identified between two pelvic pain disorders, PVD compared to irritable bowel syndrome.

Transcutaneous electrical nerve stimulation (TENS) is a non-invasive treatment to relieve pain. Contralateral TENS (i.e., TENS administered to the contralateral side of a painful body part) is beneficial when TENS cannot be directly applied to pain site, such as in cases of trauma. Although TENS produces segmental analgesia in an ipsilateral limb, it has been unclear whether TENS produces higher analgesic effects in the contralateral segmental area. The aim of present study was to investigate the analgesic effects of TENS in contralateral segmental or extra-segmental areas on physiological and subjective pain outcomes, using a nociceptive flexion reflex (NFR) method.