The purpose of this double-blinded randomized controlled trial was to investigate whether percutaneous electrolysis (PE) is able to activate endogenous pain modulation and whether its effects are dependent on the dosage of the galvanic current. A total of 54 asymptomatic subjects aged 18–40 years were randomized into three groups, receiving a single ultrasound-guided PE intervention that consisted of a needle insertion on the lateral epicondyle tendon: sham (without electrical current), low-intensity (0.3 mA, 90 s), and high-intensity (three pulses of 3 mA, 3 s). Widespread pressure pain thresholds (PPT), conditioned pain modulation (CPM), and temporal summation (TS) were assessed in the elbow, shoulder, and leg before and immediately after the intervention. Both high and low intensity PE protocols produced an increase in PPT in the shoulder compared to sham (p = 0.031 and p = 0.027). The sham group presented a significant decrease in the CPM (p = 0.006), and this finding was prevented in PE groups (p = 0.043 and p = 0.025). In addition, high-intensity PE decreased TS respect to sham in the elbow (p = 0.047) and both PE groups reduced TS in the leg (p = 0.036 and p = 0.020) without significant differences compared to sham (p = 0.512). Consequently, a single PE intervention modulated pain processing in local and widespread areas, implying an endogenous pain modulation. The pain processing effect was independent of the dosage administrated.

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.

The role of TRPA1 in the thermosensitivity of the corneal cold thermoreceptor nerve endings was studied in young and aged mice. The contribution of the TRPA1-dependent activity to basal tearing and thermally-evoked blink was also explored. The corneal cold thermoreceptors’ activity was recorded extracellularly in young (5-month-old) and aged (18-month-old) C57BL/6WT (WT) and TRPA1^−/− knockout (TRPA1-KO) mice at basal temperature (34 °C) and during cooling (15 °C) and heating (45 °C) ramps. The blink response to cold and heat stimulation of the ocular surface and the basal tearing rate were also measured in young animals using orbicularis oculi muscle electromyography (OOemg) and phenol red threads, respectively. The background activity at 34 °C and the cooling- and heating-evoked responses of the cold thermoreceptors were similar in WT and TRPA1-KO animals, no matter the age. Similar to the aged WT mice, in the young and aged TRPA1-KO mice, most of the cold thermoreceptors presented low frequency background activity, a low cooling threshold, and a sluggish response to heating. The amplitude and duration of the OOemg signals correlated with the magnitude of the induced thermal change in the WT but not in the TRPA1-KO mice. The basal tearing was similar in the TRPA1-KO and WT mice. The electrophysiological data suggest that the TRPA1-dependent nerve activity, which declines with age, contributes to detecting the warming of the ocular surface and also to integrating the thermally-evoked reflex blink.