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Offset analgesia (OA) is believed to reflect the efficiency of the endogenous pain modulatory system. However, the underlying mechanisms are still being debated. Previous research suggested both, central and peripheral mechanisms, with the latter involving the influence of specific A-delta-fibers. Therefore, this study aimed to investigate the influence of a nonischemic A-fiber conduction blockade on the OA response in healthy participants. A total of 52 participants were recruited for an A-fiber conduction blockade via compression of the superficial radial nerve. To monitor fiber-specific peripheral nerve conduction capacity, quantitative sensory testing was performed continuously. Before, during, and after the A-fiber block, an individualized OA paradigm was applied to the dorsum of both hands (blocked and control sides were randomized). The pain intensity of each heat stimulus was evaluated by an electronic visual analog scale. A successful A-fiber conduction blockade was achieved in thirty participants. OA has been verified within time (before, during, and after blockade) and condition (blocked and control side) (P < .01, d > .5). Repeated measurements analysis of variance showed no significant interaction effects between OA within condition and time (P = .24, η²p = .05). Hence, no significant effect of A-fiber blockade was detected on OA during noxious heat stimulation. The results suggest that peripheral A-fiber afferents may play a minor role in OA compared with alternative central mechanisms or other fibers. However, further studies are needed to substantiate a central rather than peripheral influence on OA. PERSPECTIVE: This article presents the observation of OA before, during, and after a successful A-fiber conduction blockade in healthy volunteers. A better understanding of the mechanisms of OA and endogenous pain modulation, in general, may help to explain the underlying aspects of pain disorders., (Copyright © 2024 United States Association for the Study of Pain, Inc. Published by Elsevier Inc. All rights reserved.)

Abstract: The coherent perceptual experience of one's own body depends on the processing and integration of signals from multiple sensory modalities, including vision, touch, and proprioception. Although nociception provides critical information about damage to the tissues of one's body, little is known about how nociception contributes to own-body perception. A classic experimental approach to investigate the perceptual and neural mechanisms involved in the multisensory experience of one's own body is the rubber hand illusion (RHI). During the RHI, people experience a rubber hand as part of their own body (sense of body ownership) caused by synchronized stroking of the rubber hand in the participant's view and the hidden participant's real hand. We examined whether the RHI can be elicited by visual and "pure" nociceptive stimulation, ie, without tactile costimulation, and if so, whether it follows the basic perceptual rules of the illusion. In 6 separate experiments involving a total of 180 healthy participants, we used a Nd:YAP laser stimulator to specifically target C and Aδ fibers in the skin and compared the illusion condition (congruent visuonociceptive stimulation) to control conditions of incongruent visuonociceptive, incongruent visuoproprioceptive, and no nociceptive stimulation. The illusion was quantified through direct (questionnaire) and indirect (proprioceptive drift) behavioral measures. We found that a nociceptive rubber hand illusion (N-RHI) could be elicited and that depended on the spatiotemporal congruence of visuonociceptive signals, consistent with basic principles of multisensory integration. Our results suggest that nociceptive information shapes multisensory bodily awareness and contributes to the sense of body ownership., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association for the Study of Pain.)

Social touch through infant holding, skin-to-skin contact, and infant carrying (babywearing) decreases infant distress and promotes secure attachment. Unknown is the extent to which these effects are the result of the activation of C-Tactile afferents (CTs), the constellation of nerve fibers associated with affective touch, primarily located in the head and trunk of the body. The purpose of the present study was to compare dynamic touch (CTs activated) to static touch (CTs less activated) during a babywearing procedure among infants experiencing Neonatal Opioid Withdrawal Syndrome (NOWS). NOWS is a spectrum of clinical symptoms, including elevated heart rate (HR), associated with withdrawal from intrauterine opioid exposure. We hypothesized that stroking an infant's head during babywearing would amplify the pleasurable effect of babywearing as measured by changes in infant HR. Twenty-nine infants in a Neonatal Intensive Care Unit (NICU) in the Southwestern USA were worn in an infant carrier starting at five days old (M = 5.4, SD = 2.6; 46.2 % White, 26.9 % Latinx, 11.5 % Native American) and physiological readings were conducted daily; heart rates of infants and caregivers were taken every 15-seconds for 5-minutes, before, during, and after babywearing (30 min per phase). Each day infants alternated (randomly) in a static touch (hands-free babywearing) or dynamic touch condition (stroking the top of the infants' head at a velocity of 3 cm/s while babywearing). On average, infants completed 3 dynamic and 3 static babywearing sessions. Hospital and research staff participated in babywearing when a parent was not available (31.0 % of infants were exclusively worn by volunteers, 27.6 % were exclusively worn by parents). We analyzed the data using Hierarchical Linear Models due to the 3-level nested design (N = 29 infants, N = 191 readings, N = 11,974 heart rates). Compared to baseline (infant calm/asleep and without contact), infant's HRs significantly declined during and after babywearing, controlling for pharmacological treatment. These effects were significantly stronger during the dynamic touch condition (reduction in HR of 11.17 bpm) compared to the static touch condition (reduction in HR of 3.74 bpm). These effects did not significantly vary by wearer (mother, father, volunteer). However, differences between the dynamic and static conditions were significantly stronger in earlier babywearing sessions, potentially indicating a learning effect. There was evidence for a calming effect among caregivers as well, particularly in the dynamic touch condition, when caregivers were engaged in active touch. Activation of CTs appears to be an important mechanism in the physiological benefits of babywearing and in the symbiotic role of caregiver-infant attachment., Competing Interests: Declaration of Competing Interest The authors do not have any conflicts of interest/competing interests. This work is funded as a result of generous financial support from BHHS Legacy Foundation, which is an Arizona charitable organization whose philanthropic mission is to enhance the quality of life and health of those it serves. This work was also funded by a grant from the Ibis Foundation. Ergobaby and Baby K’tan provided the infant carriers used in this study. All aspects of the study received IRB approval and participants actively consented to the study. All authors contributed to the manuscript development., (Published by Elsevier Inc.)

Neuronal voltage-gated KCNQ (Kv7) channels, expressed centrally and peripherally, mediate low-threshold and non-inactivating M-currents responsible for the control of tonic excitability of mammalian neurons. Pharmacological opening of KCNQ channels has been reported to generate analgesic effects in animal models of neuropathic pain. Here, we examined the possible involvement of central KCNQ channels in the analgesic effects of retigabine, a KCNQ channel opener. Behaviorally, intraperitoneally applied retigabine exerted analgesic effects on thermal and mechanical hypersensitivity in male mice developing neuropathic pain after partial sciatic nerve ligation, which was antagonized by the KCNQ channel blocker XE991 preadministered intraperitoneally and intrathecally. Intrathecally applied retigabine also exerted analgesic effects that were inhibited by intrathecally injected XE991. We then explored the synaptic mechanisms underlying the analgesic effects of retigabine in the spinal dorsal horn. Whole-cell recordings were made from dorsal horn neurons in spinal slices with attached dorsal roots from adult male mice developing neuropathic pain, and the effects of retigabine on miniature and afferent-evoked postsynaptic currents were examined. Retigabine reduced the amplitude of A-fiber-mediated EPSCs without affecting C-fiber-mediated excitatory synaptic transmission. A-fiber-mediated EPSCs remained unaltered by retigabine in the presence of XE991, consistently with the behavioral findings. The frequency and amplitude of mEPSCs were not affected by retigabine. Thus, opening of KCNQ channels in the central terminals of primary afferent A-fibers inhibits excitatory synaptic transmission in the spinal dorsal horn, most likely contributing to the analgesic effect of retigabine., Competing Interests: Declaration of competing interest The authors have declared that no conflict of interest exists., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Myelinated axons conduct action potentials, or spikes, in a saltatory manner. Inward current caused by a spike occurring at one node of Ranvier spreads axially to the next node, which regenerates the spike when depolarized enough for voltage-gated sodium channels to activate, and so on. The rate at which this process progresses dictates the velocity at which the spike is conducted and depends on several factors including axial resistivity and axon diameter that directly affect axial current. Here we show through computational simulations in modified double-cable axon models that conduction velocity also depends on extracellular factors whose effects can be explained by their indirect influence on axial current. Specifically, we show that a conventional double-cable model, with its outside layer connected to ground, transmits less axial current than a model whose outside layer is less absorptive. A more resistive barrier exists when an axon is packed tightly between other myelinated fibers, for example. We show that realistically resistive boundary conditions can significantly increase the velocity and energy efficiency of spike propagation, while also protecting against propagation failure. Certain factors like myelin thickness may be less important than typically thought if extracellular conditions are more resistive than normally considered. We also show how realistically resistive boundary conditions affect ephaptic interactions. Overall, these results highlight the unappreciated importance of extracellular conditions for axon function., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 the authors.)

Carbon nanotube (CNT) fiber electrodes have demonstrated exceptional spatial selectivity and sustained reliability in the context of intrafascicular electrical stimulation, as evidenced through rigorous animal experimentation. A significant presence of unmyelinated C fibers, known to induce uncomfortable somatosensory experiences, exists within peripheral nerves. This presence poses a considerable challenge to the excitation of myelinated Aβ fibers, which are crucial for tactile sensation. To achieve nuanced tactile sensory feedback utilizing CNT fiber electrodes, the selective stimulation of Aβ sensory afferents emerges as a critical factor. In confronting this challenge, the present investigation sought to refine and apply a rat sciatic-nerve model leveraging the capabilities of the COMSOL-NEURON framework. This approach enables a systematic evaluation of the influence exerted by stimulation parameters and electrode geometry on the activation dynamics of both myelinated Aβ and unmyelinated C fibers. The findings advocate for the utilization of current pulses featuring a pulse width of 600 μs, alongside the deployment of CNT fibers characterized by a diminutive diameter of 10 μm, with an exclusively exposed cross-sectional area, to facilitate reduced activation current thresholds. Comparative analysis under monopolar and bipolar electrical stimulation conditions revealed proximate activation thresholds, albeit with bipolar stimulation exhibiting superior fiber selectivity relative to its monopolar counterpart. Concerning pulse waveform characteristics, the adoption of an anodic-first biphasic stimulation modality is favored, taking into account the dual criteria of activation threshold and fiber selectivity optimization. Consequently, this investigation furnishes an efficacious stimulation paradigm for the selective activation of touch-related nerve fibers, alongside provisioning a comprehensive theoretical foundation for the realization of natural tactile feedback within the domain of prosthetic hand applications., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Sensory systems are shaped in postnatal life by the refinement of synaptic connectivity. In the dorsal horn of the spinal cord, somatosensory circuits undergo postnatal activity-dependent reorganization, including the refinement of primary afferent A-fiber terminals from superficial to deeper spinal dorsal horn laminae which is accompanied by decreases in cutaneous sensitivity. Here, we show in the mouse that microglia, the resident immune cells in the CNS, phagocytose A-fiber terminals in superficial laminae in the first weeks of life. Genetic perturbation of microglial engulfment during the initial postnatal period in either sex prevents the normal process of A-fiber refinement and elimination, resulting in an altered sensitivity of dorsal horn cells to dynamic tactile cutaneous stimulation, and behavioral hypersensitivity to dynamic touch. Thus, functional microglia are necessary for the normal postnatal development of dorsal horn sensory circuits. In the absence of microglial engulfment, superfluous A-fiber projections remain in the dorsal horn, and the balance of sensory connectivity is disrupted, leading to lifelong hypersensitivity to dynamic touch., (Copyright © 2023 Xu et al.)