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Vladimir N Nikolenko,1,2 Ekaterina M Shelomentseva,2 Maria M Tsvetkova,2 Elina I Abdeeva,1 Dmitriy B Giller,1 Juliya V Babayeva,1 Evgeny E Achkasov,1 Liliya V Gavryushova,3 Mikhail Y Sinelnikov1,4 1First Moscow State Medical University Named After I.M. Sechenov (Sechenov University), Moscow, 119991, Russia; 2Lomonosov Moscow State University, Moscow, 119991, Russia; 3Saratov State Medical University, Saratov, Russian Federation; 4Research Institute of Human Morphology, Moscow, 119901, Russian FederationCorrespondence: Mikhail Y Sinelnikov, Sechenov University, Trubetskaya 8, Moscow, 119991, Russian Federation, Tel/Fax +7 89199688587, Email sinelnikov_m_e@staff.sechenov.ruAbstract: The human body is constantly under the influence of numerous pathological factors: both external and internal. These factors can be potentially harmful and are perceived as such with a specialized nervous system subunit: the nociceptive system. The functional unit of the nociceptive system is the nociceptor. Recent studies have shown that nociceptors play a crucial role in maintaining of defensive homeostasis (responsive, immune, behavioral). Nociceptors respond to potentially harmful stimuli within viscera, bones, muscles, skin and specialized sensory organs. They function as complex predictors of harm through formation of pain stimulus. Their function and structures vary within different tissues. This variability reflects the anatomical and pathological peculiarities of varying tissues. Nociceptors play a significant role in adaptive, protective and behavioral reactions. Their functional capabilities and vast spread throughout the body make them the main units of the body’s defense system, allowing us to interact with the inner and outer environments.Keywords: nociceptors, defensive homeostasis, tissue specific variability, pain perception

Gerardo Beltran Serrano,1– 3 Laura Pooch Rodrigues,2 Bruno Schein,1,2 Maxciel Zortea,1,2 Iraci Lucenada Silva Torres,1,4,5 Felipe Fregni,6 Wolnei Caumo1,2,5 1Post-Graduate Program in Medical Sciences, School of Medicine, Universidade Federal Do Rio Grande Do Sul (UFRGS), Porto Alegre, Brazil; 2Laboratory of Pain and Neuromodulation at Hospital De Clínicas De Porto Alegre (HCPA), Porto Alegre, Brazil; 3Psychology Department, Universidad Catolica De Cuenca, UCACUE, Cuenca, Ecuador; 4Department of Pharmacology, Institute of Health Sciences (ICBS), Universidade Federal Do Rio Grande Do Sul (UFRGS), Porto Alegre, Brazil; 5Pharmacology of Pain and Neuromodulation: Pre-Clinical Investigations Research Group, Universidade Federal Do Rio Grande Do Sul (UFRGS), Porto Alegre, Brazil; 6Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USACorrespondence: Wolnei Caumo Fax + (55) 51- 3359.8083Email wcaumo@hcpa.edu.brObjective: We evaluated whether active(a)-tDCS combined with hypnotic analgesia suggestion (HS) would be more effective than a single active(a)-tDCS, and/or sham-(s)-tDCS and s-tDCS/HS on the following outcomes: function of descending pain modulatory system (DPMS) during the conditioned pain modulation test (CPM-test) (primary outcome), heat pain threshold (HPT), heat pain tolerance (HPTo) and cold pressor test (CPT) (secondary outcomes). We also examined whether their effects are related to neuroplasticity state evaluated by serum brain-derived-neurotropic factor (BDNF).Materials and Methods: Forty-eight females received one session of one of the four interventions (a-tDCS/HS, s-tDCS/HS, a-tDCS, and s-tDCS) in an incomplete randomized crossover sequence. The a-tDCS or s-tDCS was applied over the left dorsolateral prefrontal cortex (DLPFC) for 30 minutes at 2mA.Results: A generalized linear model revealed a significant main effect for the intervention group (P < 0.032). The delta-(Δ) pain score on the Numerical Pain Scale (NPS0-10) during CPM-test in the a-tDCS/HS group was − 0.25 (0.43). The (Δ) pain score on NPS (0– 10) during CPM-test in the other three groups was a-tDCS=− 0.54 (0.41), HS − 0.01 (0.41) and s-tDCS/HS=− 0.19 (0.43). A-tDCS/HS intervention increased the CPT substantially compared to all other interventions. Also, higher baseline levels of BDNF were associated with a larger change in CPT and HPTo.Conclusion: These findings indicate that the HS combined with a-tDCS mitigated the effect of the a-tDCS on the DPMS. The a-tDCS up-regulates the inhibition on DPMS, and the HS improved pain tolerance. And, together they enhanced the reaction time substantially upon the CPT.Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT03744897.Keywords: tDCS, hypnotic analgesia, conditioned pain modulation, pain perception