Accepted

Electrical stimulation of skin nociceptors is gaining attention in pain research and peripheral neuropathy diagnosis. However, the optimal parameters for selective stimulation are still difficult to determine because they require simultaneous characterization of the electrical response of small fibers (Aδ- and C-fibers). In this study, we measured the electrical threshold responses of small fibers to train-pulse stimulation in humans for the first time. We also examined selective stimulation a computational model, which combines electrical analysis, and terminal fiber and synaptic models, including the first cutaneous pain C-fiber model. Selective stimulation of small fibers is performed by injecting train-pulse stimulation coaxial electrodes with an intraepidermal needle tip at varying pulse counts and frequencies. The activation Aδ- or C-fibers was discriminated from the differences in reaction time. Aδ-fiber elicited a pinpricking sensation with a mean reaction time of 0.522 s, and C-fiber elicited a tingling sensation or slight burning itch with a mean reaction time of 1.243 s. The implemented multiscale electrical model investigates synaptic effects while considering stimulation waveform characteristics. Experimental results showed that perception thresholds decreased with the number of consecutive pulses and frequency up to convergence (five pulses or 70 Hz) during the selective stimulation of Aδ- and C-fibers. Considering the synaptic properties, the optimal stimulus conditions for selective stimulation of Aδ- vs. C-fibers were train of at least four pulses and a frequency of 40-70 Hz at a pulse width of 1 ms. The experimental results were modeled with high fidelity by incorporating temporal synaptic effects into the computational model. Numerical analysis revealed terminal axon thickness to be the most important biophysical factor affecting threshold variability. The computational model can be used to estimate perception thresholds while understanding the mechanisms underlying the selective stimulation of small fibers. The parameters derived here are important in exploring selective stimulation between Aδ- and C-fibers for diagnosing neuropathies.

To estimate the magnitude of the nocebo response and explore its influencing factors in irritable bowel syndrome (IBS).

Over the past 15 years, the research field on Mas-related G protein-coupled receptors (Mrgprs), a relatively new family of rhodopsin A-like G protein-coupled receptors, has expanded enormously, and a plethora of recent studies have provided evidence that several of these Mrgpr family members play an important role in the underlying mechanisms of itch and pain, as well as in the initiation and modulation of inflammatory/allergic responses. Initial studies mainly focused on the skin, but more recently also visceral organs such as the respiratory and gastrointestinal (GI) tracts emerged as sites for Mrgpr involvement. It has become clear that the gastrointestinal tract and its innervation in close association with the immune system represent a novel expression site for Mrgprs where they contribute to the interoceptive mechanisms maintaining homeostasis and might constitute promising targets in chronic abdominal pain disorders. In this short review, we provide an update of our current knowledge on the expression, distribution, and function of members of this Mrgpr family in intrinsic and extrinsic neuro-immune pathways related to the gastrointestinal tract, their mediatory role(s) in gut neuro-immune signaling, and their involvement in visceral afferent (nociceptive) pathways.

The spinal dorsal horn plays a crucial role in the transmission and processing of somatosensory information. Although spinal neural circuits that process several distinct types of somatic sensations have been studied extensively, those responsible for visceral pain transmission remain poorly understood. In the present study, we analyzed dextran sodium sulfate (DSS)-induced inflammatory bowel disease (IBD) mouse models to characterize the spinal dorsal horn neurons involved in visceral pain transmission. Immunostaining for c-fos, a marker of neuronal activity, demonstrated that numerous c-fos-positive cells were found bilaterally in the lumbosacral spinal dorsal horn, and their distribution was particularly abundant in the shallow dorsal horn. Characterization of these neurons by several molecular markers revealed that the percentage of the Pit1-Oct1-Unc86 domain (POU domain)-containing transcription factor Brn3a-positive neurons among the c-fos-positive neurons in the shallow dorsal horn was 30%-40% in DSS-treated mice, which was significantly higher than that in the somatic pain model mice. We further demonstrated by neuronal tracing that, within the shallow dorsal horn, Brn3a-positive neurons were more highly represented in spino-solitary projection neurons than in spino-parabrachial projection neurons. These results raise the possibility that Brn3a-positive spinal dorsal horn neurons make a large contribution to visceral pain transmission, part of which is mediated through the spino-solitary pathway.

Postoperative nausea and vomiting (PONV) is a still highly relevant problem and is known to be a distressing side effect in patients. The aim of this study was to develop a machine learning model to predict PONV up to 24 h with fentanyl-based intravenous patient-controlled analgesia (IV-PCA).

Calcitonin gene-related peptide (CGRP) pathway-targeted treatments have been shown to be efficacious in the prevention of episodic and chronic migraine. Currently approved therapies include monoclonal antibodies (mAbs) that target CGRP (eptinezumab, fremanezumab, and galcanezumab) and the CGRP receptor (erenumab), and small molecule CGRP receptor antagonists (atogepant and rimegepant). While CGRP pathway-targeted treatments are generally well-tolerated, in a review article by Holzer and Holzer-Petsche published in the January 2022 issue of the authors discussed the role of the CGRP pathway in gastrointestinal physiology, with a specific focus on constipation associated with the use of CGRP pathway-targeted treatments. The authors state that real-world surveys have shown constipation to be a "major adverse event" reported in "more than 50% of patients treated with erenumab, fremanezumab or galcanezumab." As described in the current commentary, the limited data from the cited references in the review article by Holzer and Holzer-Petsche do not support that statement.