+ current/channel; K CA , Ca 2+ -gated K + current/ channel; K V , voltage-gated K + current/channel; NHR, nasal hyperreactivity; NO, nitric oxide; ORAI1, calcium release-activated calcium channel protein 1; STIM1, stromal interaction molecule 1; TREK1, TWIK-related K+ channel 1; TRPV1, transient receptor potential channel vanilloid 1.
Peripheral sensory neurons transduce physicochemical stimuli affecting somatic tissues into the firing of action potentials that are conveyed to the central nervous system. This results in conscious perception, adaptation, and survival, but alterations of the firing patterns can result in pain and hypersensitivity conditions. Thus, understanding the molecular mechanisms underlying action potential firing in peripheral sensory neurons is essential in sensory biology and pathophysiology. Over the past 30 years, it has been consistently reported that these cells can display membrane potential instabilities (MPIs), in the form of subthreshold membrane potential oscillations or depolarizing spontaneous fluctuations. However, research on this subject remains sparse, without a clear conductive thread to be followed. To address this, we here provide a synthesis of the description, molecular bases, mathematical models, physiological roles, and pathophysiological implications of MPIs in peripheral sensory neurons. Membrane potential instabilities have been reported in trigeminal, dorsal root, and Mes-V ganglia, where they are believed to support repetitive firing. They are proposed to have roles also in intercellular communication, ectopic firing, and responses to tonic and slow natural stimuli. We highlight how MPIs are of great interest for the study of sensory transduction physiology and how they may represent therapeutic targets for many pathological conditions, such as acute and chronic pain, itch, and altered sensory perceptions. We identify future research directions, including the elucidation of the underlying molecular determinants and modulation mechanisms, their relation to the encoding of natural stimuli and their implication in pain and hypersensitivity conditions.
Background Electrical stimulation of skin afferents can induce somatosensory plasticity in humans. Nevertheless, it is unknown if this is possible to do through percutaneous stimulation of a peripheral nerve, which will allow for regional anaesthesia interventions. Furthermore, potentiation protocols applied over mainly non‐nociceptive fibres inhibit nociception in rodents, but this has not been tested in humans. Objective To determine whether a protocol aiming to depress the nociceptive circuit and another aiming to potentiate non‐nociceptive circuits produce regional hypoalgesia and changes in motor function, applied through percutaneous peripheral nerve stimulation (pPNS), and to assess which of them is more promising for pain relief, immediately and 24 h after the intervention. Methods PT‐cLF protocol aims to depress the nociceptive pathway through Pain Threshold, continuous Low Frequency stimulation and ST‐bHF aims to produce potentiation of the non‐nociceptive pathway, through Sensory Threshold burst stimulation at High Frequency. All subjects (n = 29) went through both protocols and a control condition in a randomized and blinded crossover design. Results Compared to control, ST‐bHF induced distal hypoalgesia, towards electrical (p = 0.04) and mechanical stimuli (p = 0.02) and produced mechanical hypoesthesia (p = 0.02). Contrarily, hypoalgesia was not observed after PT‐cLF (p > 0.05) but increased electrical motor threshold (p = 0.04), reduced motor recruitment (p = 0.03), and the subjects reported feeling reduced strength (p < 0.01). Conclusion This works provides evidence that is possible to induce antinociceptive plasticity in a wide territory using pPNS. Moreover, it demonstrates for the first time in humans that a protocol aiming to produce long‐term potentiation applied predominantly over non‐nociceptive afferents induces hypoesthesia and hypoalgesia.
Transcranial direct current stimulation (tDCS) has been investigated as a way of improving motor learning. Our purpose was to explore the reversal bilateral tDCS effects on manual dexterity training, during five days, with the retention component measured after 5 days to determine whether somatosensory effects were produced. In this randomized, triple-blind clinical trial, 28 healthy subjects (14 women) were recruited and randomized into tDCS and placebo groups, although only 23 participants (13 women) finished the complete protocol. Participants received the real or placebo treatment during five consecutive days, while performing a motor dexterity training program of 20 min. The motor dexterity and the sensitivity of the hand were assessed pre- and post-day 1, post 5 days of training, and 5 days after training concluded. Training improved motor dexterity, but tDCS only produced a tendency to improve retention. The intervention did not produce changes in the somatosensory variables assessed. Thus, reversal bi-tDCS had no effects during motor learning on healthy subjects, but it could favor the retention of the motor skills acquired. These results do not support the cooperative inter-hemispheric model.
The class IIa histone deacetylases (HDACs) have pivotal roles in the development of different tissues. Of this family, Schwann cells express Hdac4, 5 and 7 but not Hdac9. Here we show that a transcription factor regulated genetic compensatory mechanism within this family of proteins, blocks negative regulators of myelination ensuring peripheral nerve developmental myelination and remyelination after injury. Thus, when Hdac4 and 5 are knocked-out from Schwann cells in mice, a JUN-dependent mechanism induces the compensatory overexpression of Hdac7 permitting, although with a delay, the formation of the myelin sheath. When Hdac4,5 and 7 are simultaneously removed, the Myocyte-specific enhancer-factor d (MEF2D) binds to the promoter and induces the de novo expression of Hdac9, and although several melanocytic lineage genes are misexpressed and Remak bundle structure is disrupted, myelination proceeds after a long delay. Thus, our data unveil a finely tuned compensatory mechanism within the class IIa Hdac family, coordinated by distinct transcription factors, that guarantees the ability of Schwann cells to myelinate during development and remyelinate after nerve injury.
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