Top-Down Effect of Direct Current Stimulation on the Nociceptive Response of Rats

Abstract

Transcranial direct current stimulation (tDCS) is an emerging, noninvasive technique of neurostimulation for treating pain. However, the mechanisms and pathways involved in its analgesic effects are poorly understood. Therefore, we investigated the effects of direct current stimulation (DCS) on thermal and mechanical nociceptive thresholds and on the activation of the midbrain periaqueductal gray (PAG) and the dorsal horn of the spinal cord (DHSC) in rats; these central nervous system areas are associated with pain processing. Male Wistar rats underwent cathodal DCS of the motor cortex and, while still under stimulation, were evaluated using tail-flick and paw pressure nociceptive tests. Sham stimulation and naive rats were used as controls. We used a randomized design; the assays were not blinded to the experimenter. Immunoreactivity of the early growth response gene 1 (Egr-1), which is a marker of neuronal activation, was evaluated in the PAG and DHSC, and enkephalin immunoreactivity was evaluated in the DHSC. DCS did not change the thermal nociceptive threshold; however, it increased the mechanical nociceptive threshold of both hind paws compared with that of controls, characterizing a topographical effect. DCS decreased the Egr-1 labeling in the PAG and DHSC as well as the immunoreactivity of spinal enkephalin. Altogether, the data suggest that DCS disinhibits the midbrain descending analgesic pathway, consequently inhibiting spinal nociceptive neurons and causing an increase in the nociceptive threshold. This study reinforces the idea that the motor cortex participates in the neurocircuitry that is involved in analgesia and further clarifies the mechanisms of action of tDCS in pain treatment.

Primary Motor Cortex Transcranial Direct Current Stimulation Modulates Temporal Summation of the Nociceptive Withdrawal Reflex in Healthy Subjects

“…Pharmacological studies in rodents have shown that manipulation of descending control pathways can activate a top-down inhibition of WDR neuron excitability associated with pain hypersensitivity [55,56]. Another animal study demonstrated that M1 tDCS can cause a disinhibition of the PAG and changes in dorsal horn nociceptive processing [54]. In line with this, it is likely that the results seen here are a due to an indirect modulation of WDR excitability by M1 tDCS manifesting as a reduced TS of the NWR response.…”

“…These studies have shown tDCS is associated with activation of the mu-opioid receptor system in the PAG and that analgesia could be reversed by opioid antagonists. These strands of evidence suggest that that M1 tDCS can cause top-down changes in the functional connectivity in pain related brain and brainstem regions which may activate descending control pathways [54]. Therefore, we addressed the question of whether M1 tDCS could indirectly modulate spinal nociceptive processing by investigation the topdown influence on the TS of pain.…”

“…It has not yet been established which brain regions might mediate these effects, however, it is likely that there is a top-down modulation of spinally-projecting endogenous analgesic systems by tDCS applied over M1 [54]. It has been suggested that that the effects of tDCS may be enhanced when combined with peripheral nerve stimulation [17] or tests that induce diffuse noxious inhibitory control (DNIC) and that analgesic efficacy may be dependent on the bottom-up activation of spino-bulbospinal loops [19,20].…”

Memory and Cognition-Related Neuroplasticity Enhancement by Transcranial Direct Current Stimulation in Rodents: A Systematic Review

“…The comprehensive revision of the effect of tDCS on rodent models of normal and pathological brain functioning does therefore provide a novel contribution to the field. Overall, the revised studies indicated that tDCS was able to modulate synaptic plasticity and, consequently, learning and memory processes [87,88].…”

Anodal and cathodal tDCS modulate neural activity and selectively affect GABA and glutamate syntheses in the visual cortex of cats

“…In recent decades, several non-invasive neuromodulatory approaches have been established that have allowed us to manipulate brain activity and develop a therapeutic paradigm for treating brain diseases (Moliadze et al 2003;Kim et al 2015;Ding et al 2016;Gschwind & Seeck, 2016;Lenz et al 2016;Khatoun et al 2017;Kozyrev et al 2018). Transcranial direct current stimulation (tDCS) is a non-invasive tool that can reversibly modulate brain activity by applying a weak, constant direct current through the scalp or skull (Nitsche & Paulus, 2000;Dimov et al 2016;Zmigrod et al 2016;Mosayebi Samani et al 2019). Accumulating evidence has demonstrated that polarity-specific tDCS can improve motor performance (Amadi et al 2015;Karok et al 2016), modulate cognitive or perceptual function (Spiegel et al 2012;Spiegel et al 2013;Labbe et al 2016;Price et al 2016;Rosen et al 2016;Weigl et al 2016;Zmigrod et al 2016;Bruckner & Kammer, 2017;Hertenstein et al 2019;Wiegand et al 2019;Xiong et al 2019;Salvi et al 2020), and facilitate learning and memory (Choe et al 2016;Sandrini et al 2016;Van Meel et al 2016;Ke et al 2019;Nissim et al 2019;Gibson et al 2020).…”