Behavior and electrophysiology studies of the peripheral neuropathy induced by individual and co-administration of paclitaxel and oxaliplatin in rat.

AIMS: Antitumor agents, as taxanes and platinum compounds, induce peripheral neuropathies which can hamper their use for cancer treatment. The study of chemotherapy-induced neuropathies in humans is difficult because of ethical reasons, differences among administration protocols and intrinsic characteristics of patients. The aim of the present study is to compare the neuropathic signs induced by individual or combined administration of paclitaxel and oxaliplatin. MAIN METHODS: Oxaliplatin and paclitaxel were administered individually and combined to induce peripheral neuropathy in rats, sensory neuropathic signs were assessed in the hind limbs and orofacial area. The in vitro skin-saphenous nerve preparation was used to record the axonal activity of Aδ sensory neurons. KEY FINDINGS: Animals treated with the combination developed mechanical allodynia in the paws and muscular hyperalgesia in the orofacial area, which was similar to that in animals treated with monotherapy, the latter also developed cold allodynia in the paws. Aδ-fibers of the rats treated with the combination were hyperexcited and presented hypersensitivity to pressure stimulation of the innervated skin, also similar to that recorded in the fibers of the animals treated with monotherapy. SIGNIFICANCE: Our work objectively demonstrates that the combination of a platinum compound with a taxane does not worsen the development of sensorial neuropathies in rats, which is an interesting data to take into account when the combination of antitumor drugs is necessary. Co-administration of antitumor drugs is more effective in cancer treatment without increasing the risk of the disabling neuropathic side effects.

Chronic pain and cannabinoids. Great expectations or a christmas carol.

The discovery of the endocannabinoid system nearly three decades ago generated great interest among pain scientists. Moreover, its analogy with the opioid system in terms of evolutionary preservation, tissue localization and analgesic activity enabled a vast new field for the development of medicines addressed to those types of pain that still nowadays are difficult to manage. However, the main disadvantage that hampers the use of cannabinergic drugs as analgesics is their identification with recreational use, besides their psychotomimetic actions. Pain has traditionally been classified attending to the ailment duration (acute or chronic) and drugs are used according to the intensity of the pain to treat, but it is also important to target the mechanism involved despite the intensity or duration of pain. The present chapter reviews the study and use of cannabinoids attending separately to four classic types of pain: nociceptive, inflammatory, neuropathic and oncological, considering basic research (pain animal models) as well as clinical practice.

Blockade of sigma 1 receptors alleviates sensory signs of diabetic neuropathy in rats.

BACKGROUND: E-52862 (S1RA, 4-[2-[[5-methyl-1-(2-naphthalenyl)-1H-pyrazol-3-yl]oxy]ethyl]-morpholine), a novel selective sigma 1 receptor (σ1R) antagonist, has demonstrated efficacy in nociceptive and neuropathic pain models. Our aim was to test if σ1R blockade with E-52862 may modify the signs of neuropathy in Zucker diabetic fatty (ZDF) rats, a type 2 diabetes model. METHODS: Mechanical and thermal response thresholds were tested on 7-, 13-, 14- and 15-week-old ZDF rats treated with saline or with E-52862 acutely administered on week 13, followed by sub-chronic administration (14 days). Axonal peripheral activity (skin-saphenous nerve preparation) and isolated aorta or mesenteric bed reactivity were analysed in 15-week-old ZDF rats treated with saline or E-52862 and in LEAN rats. RESULTS: Zucker diabetic fatty rats showed significantly decreased thermal withdrawal latency and threshold to mechanical stimulation on week 13 compared to week 7 (prediabetes) and with LEAN animals; single-dose and sub-chronic E-52862 administration restored both parameters to those recorded on week 7. Regarding axonal peripheral activity, E-52862 treatment increased the mean mechanical threshold (77.3 ± 21 mN vs. 19.6 ± 1.5 mN, saline group) and reduced the response evoked by mechanical increasing stimulation (86.4 ± 36.5 vs. 352.8 ± 41.4 spikes) or by repeated mechanical supra-threshold steps (39.4 ± 1.4 vs. 83.5 ± 0.9). E-52862 treatment also restored contractile response to phenylephrine in aorta and mesenteric bed. CONCLUSIONS: E-52862 administration reverses neuropathic (behavioural and electrophysiological) and vascular signs in the ZDF rat. SIGNIFICANCE: Blockade of σ1R avoids the development of diabetic neuropathy in rats, and may represent a potentially useful therapeutic approach to peripheral neuropathies in diabetic patients. WHAT DOES THIS STUDY ADD?: This study presents evidences for the potential usefulness of sigma receptor blockade on diabetic neuropathy in rats. The methodology includes behavioural evidences, electrophysiological data and vascular-isolated models.

Influence of pertussis toxin on the calcitonin-opioid interaction in isolated tissues.

1. In order to clarify one of the mechanisms involved in the analgesic effect of calcitonin, we have tested the in vitro modifications induced by calcitonin on the effect of opioids. 2. The inhibition of the contractions induced by opioids or clonidine, in guinea-pig ileum or in mouse vas deferens, were significantly reduced in tissues incubated with pertussis toxin (PTX). When tissues were incubated with PTX and calcitonin, the inhibitory effect was restored. 3. These results suggest that calcitonin is able to potentiate a non-PTX-sensitive mechanism of transduction and support the possibility of involvement of similar G-proteins in the effects of opioid and alpha 2-adrenoceptor agonists.

Study of mechanisms of calcitonin analgesia in mice. Involvement of 5-HT3 receptors.

The analgesic effect of calcitonin when serotonin (5-HT) concentration is increased and the involvement of some 5-HT receptors were studied using the writhing test in mice. 5-hydroxytryptophan (5-HTP) administration increased both 5-HT levels in the central nervous system (CNS) and calcitonin analgesia. The 5-HT(1A) agonist (+/-)-8-hydroxy-2-dipropylaminotetralin hydrobromide (8-OH-DPAT) diminished calcitonin analgesia, this effect being antagonised by the 5-HT(1A) antagonist (WAY 100, 135). As the stimulation of 5-HT(1A) autoreceptors reduces the turnover of 5-HT, the effect of 8-OH-DPAT on calcitonin analgesia may be attributed to this decrease. The 5-HT(2A-2C) agonist (+/-)-1-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane hydrochloride (DOI) diminished calcitonin analgesia. A sub-analgesic dose of the 5-HT(2A) antagonist ketanserin failed to prevent this effect. The 5-HT(3) agonist (+/-)-2-methyl-5-hydroxytryptamine maleate (2-methyl-5-HT) potentiated calcitonin analgesia, whereas it was significantly reduced by the 5-HT(3) antagonist tropisetron. The effect of 2-methyl-5-HT on calcitonin analgesia was also reversed by tropisetron, This result suggests that the 5-HT(3) receptor may play an important role in the relationship between calcitonin and the serotonergic system. Tropisetron also reversed the analgesia induced by calcitonin plus 5-HTP corroborating importance of the 5-HT(3) receptors.

Analgesic effect of salmon-calcitonin administered by two routes. Effect on morphine analgesia.

We compared the analgesia induced by intraperitoneally (i.p.) and intracerebroventricularly (i.c.v.) administered salmon-calcitonin (S-CT), using the hot-plate test and the writhing test. The influence of the route of administration on the analgesia induced by morphine was also studied. After i.p. administration the analgesic effect was observed only in the writhing test. When S-CT was administered i.c.v., analgesia was observed in both tests, although it was greater in the writhing test than in the hot-plate test. I.c.v. injected S-CT increased the analgesia of i.p. injected morphine. Our results provide new information about the analgesic effect of S-CT and suggest that central mechanisms are involved.

Involvement of central serotonergic pathways in analgesia elicited by salmon calcitonin in the mouse.

The contribution of central serotonergic pathways to the analgesic activity induced by salmon calcitonin in the writhing test was investigated. Salmon calcitonin was administered to mice after lesioning of the ascending and descending serotonergic pathways by means of i.p. administration of p-chloroamphetamine (40 mg/kg, for 2 days) or p-chlorophenylalanine (300 mg/kg, for 3 days). The analgesic effect induced by salmon calcitonin at the doses of 10 and 20 IU/kg was not evident in mice previously treated with p-chloroamphetamine or p-chlorophenylalanine. However, the analgesic effect of salmon calcitonin 40 IU/kg was not significantly modified by p-chloroamphetamine or p-chlorophenylalanine pretreatment. Salmon calcitonin did not alter the depletion of 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid after p-chloroamphetamine or p-chlorophenylalanine administration. Similarly, this hormone did not change the NSD 1015-induced accumulation of 5-hydroxytryptophan or the tranylcypromine-induced accumulation of 5-HT. These results indicate that although salmon calcitonin does not influence the synthesis and metabolism of 5-HT, it does require the integrity of the serotonergic system in order to cause analgesia.

Blockade of Gi/o proteins modifies electrical activity of S-myenteric neurons from guinea-pig ileum.

We have investigated the effect of blockade of G(i/o) proteins on the electrical activity of S-myenteric neurons from guinea-pig ileum longitudinal muscle-myenteric plexus preparations. Intracellular recordings were made from either control or pertussis toxin (PTX) treated tissues. PTX is known to disrupt the function of G(i/o) proteins. Incubation with PTX (300 ng/ml) induced three main changes in the electrophysiological characteristics of S-neurons: (1) resting membrane potential was more depolarised; (2) fast excitatory postsynaptic potentials (EPSPs) were faster and narrower; and (3) spontaneous fast EPSPs and action potentials were more frequent. Amplitude of slow EPSPs was not modified. This general increase in excitability after blockade of G(i/o) proteins shares characteristics with the slow depolarisation induced by long-lasting trains of low-frequency electrical stimulation and could be mediated by similar mechanisms. Electrophysiological activity of S-myenteric neurons could be modulated by an inhibitory tone, which PTX could modify by either pre- or post-synaptic mechanisms, such as inhibition of the tonic release of inhibitory neurotransmitters and/or intracellular signal transduction involving PTX-sensitive G(i/o) proteins.

Blockade by pertussis toxin of the opioid effect on guinea pig ileum. Contractility and electrophysiological neuronal recording.

The aim of the present study was to analyse the correlation between functional and electrophysiological effects of the opioids in guinea pig ileum. Preparations of guinea pig ileum myenteric plexus-longitudinal muscle strips were used to compare the effect of two opioids, morphine (a mu-agonist) and U-50,488H (a kappa-agonist) on the electrically-induced contractile response and the excitatory postsynaptic potentials exhibited by the myenteric neurones when the internodal strands are electrically stimulated. Both opioids dose-dependently inhibited the contractile responses and the fast excitatory postsynaptic potentials (fEPSPs) in S neurones but did not modify the amplitude of the slow postsynaptic potentials. Pertussis toxin pretreatment was able to antagonise the effects of both morphine and U-50,448H. From our results it can be suggested that the effect of the opioids on guinea pig ileum involves the inhibition of neuronal fEPSPs.

The involvement of 5-HT3 and 5-HT4 receptors in two models of gastrointestinal transit in mice.

Our aim was to study the involvement of 5-hydroxytryptamine (5-HT)(3) and 5-HT(4) receptors in two models of gastrointestinal transit (GIT) in mice: the 5-hydroxytryptophan (5-HTP)-induced diarrhea and intestinal inflammation produced by an irritant agent, croton oil (CO). 5-HTP (10 mg/kg) produced diarrhea that was significantly inhibited after pretreatment with ondansetron (5-HT(3) antagonist) or RS 39604 (5-HT(4) antagonist) (1-5 mg/kg). The GIT speed was increased after CO and 5-HTP administration. 5-HT(3-4) antagonists decreased GIT after 5-HTP-treatment but not after CO-treatment. Our results show that 5-HT(3) and 5-HT(4) receptors are involved in 5-HTP-induced diarrhea. This may be the reason why 5-HT(3-4) antagonists could be useful in the treatment of carcinoid syndrome diarrhea. 5-HT(3-4) antagonists were not effective in the modifications of GIT; nevertheless, they could be useful in the treatment of inflammatory bowel diseases because some symptoms as abdominal pain, discomfort or abnormal bowel function are modulated via 5-HT(3).

Effect of salmon-calcitonin on the analgesic effect of selective mu, delta and kappa opioid agonists in mice.

The analgesic effect of three different opioid agonists, DAMGO ([D-Ala2,N-Me-Phe4,Gly5-ol]enkephalin), U-50,488H (trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidynyl)cyclohexyl] benzene-aceramide methane sulphonate), and [D,Pen2-D,Pen5]-enkephalin, which act upon mu, delta and kappa opioid receptors, respectively, was compared in the presence and absence of salmon-calcitonin (s-CT). The analgesic test used was the writhing test in mice. The analgesic effect of the opioids was significantly enhanced by pretreatment of the animals with s-CT intraperitoneally (i.p.) administered. This effect was more evident for the delta and kappa-agonists. The present result suggests that the joint administration of s-CT and opioids may be a useful and interesting alternative in the treatment of painful diseases resistant to other treatments.

Effect of butanedione monoxime on the contractility of guinea pig ileum and on the electrophysiological activity of myenteric S-type neurones.

2,3-Butanedione monoxime (BDM) has demonstrated protective effects on isolated cardiac tissues, and on smooth muscle but its mechanism of action is not fully understood. To simultaneously study the effect of BDM on muscle contractility and on neuronal activity, the effect of BDM was tested in the contractile force of myenteric plexus-longitudinal muscle strips and in electrophysiological activity of myenteric S-type neurones of guinea pig ileum. BDM reduces, in a dose-dependent manner, the force of the spontaneous motility and the contractions induced by acetylcholine, bethanechol and electrical stimulation. The same BDM concentrations depolarize the neuronal membrane and reduce the rate of evoked firing. The effect of BDM can be attributed to a direct effect on the smooth muscle and to modifications of the neuronal activity.

Calcitonin reverts pertussis toxin blockade of the opioid analgesia in mice.

The aim of this paper is to study the influence of salmon calcitonin (SCT) on opioid analgesia when opioid transduction pathways are functionally uncoupled from Gi/o proteins by treatment with pertussis toxin (PTX). The antinociceptive effect of morphine and three selective opioid agonists, [D-Ala2,N-Me-Phe2,Gly5-ol]enkephalin (DAMGO) (OP(3-mu receptor agonist), [D-Pen2.5]-enkephalin (OP-1-delta receptor agonist) and trans-( +/- )-3,4-dichloro-N-methyl-N-[2-1(-pyrrolidinyl)-cyclohexyl]-benzene-acetam ide methane sulfonate (U-50, 488H) (OP1-kappareceptor agonist) was evaluated, using the tail flick test, in mice treated with PTX or with PTX and SCT. PTX blocked the antinociceptive effect of the opioids, being the antinociception similar in control animals and in mice treated with PTX and SCT. Thus, SCT prevents the effect of the blockade of Gi/o-proteins. From this it could be suggested that calcitonin activates alternative antinociceptive mechanisms that are not dependent on Gi/o-proteins.

In vitro study of the interaction of salmon calcitonin with mu, delta and kappa opioid agonists.

A possible interaction of salmon-calcitonin with opioid systems was studied in isolated tissues. Neurogenic contractions were elicited by electrical stimulation in guinea-pig ileum myenteric plexus-longitudinal muscle strips, rabbit vas deferens and mouse vas deferens. Bremazocine inhibited neurogenic contractions in all three tissues (presumably through kappa-receptors) [D-Pen2, D-Pen5]enkephalin and [Met5]enkephalin inhibited contractions in mouse vas deferens (presumably through delta-receptors), and [D-Ala2, N-Me-Phe4, Gly5-ol]enkephalin (DAMGO) inhibited contractions in guinea-pig ileum and mouse vas deferens (presumably through mu-receptors). All inhibitory effects were concentration-dependent. Salmon-calcitonin 0.1 IU/ml increased the effect of bremazocine in guinea-pig ileum and rabbit vas deferens and also increased the effects of [D-Pen2, D-Pen5]enkephalin and [Met5]enkephalin in mouse vas deferens. In contrast, salmon-calcitonin up to 0.4 IU/ml did not change the effect of bremazocine in mouse vas deferens and the effect of DAMGO in guinea-pig ileum and mouse vas deferens. It is concluded that salmon-calcitonin enhances agonist effects at opioid kappa- and delta- but not at opioid mu-receptors. The level of this interaction remains to be elucidated. The interaction may be the basis of the analgesic effect of salmon-calcitonin in vivo.

Salmon calcitonin potentiates the analgesia induced by antidepressants.

Antidepressants are used in the treatment of a variety of pain syndromes. Most of them act by blocking noradrenaline (NA) and serotonin (5-HT) reuptake. It is also well known that the serotonergic system is also involved in calcitonin (CT) analgesia. Taking these two evidences into account, the modification of the analgesic effect of nortriptyline, amitriptyline, and paroxetine in the presence of salmon CT (s-CT) was examined in mice. The forced-swimming test was carried out in order to choose doses of each drug that did not induce an antidepressant effect under our experimental conditions (nortriptyline: 0.2-5 mg/kg ip, amitriptyline: 2.5-20 mg/kg ip, and paroxetine: 5-30 mg/kg ip). The analgesic effect of each antidepressant was then evaluated using the acetic acid test. At the doses tested, the antidepressants induced a dose-dependent analgesic effect. When mice were pre-treated with a subanalgesic dose of s-CT (2.5 IU/kg), the analgesic effect of amitriptyline and paroxetine was significantly increased though no modification was found for nortriptyline. In summary, s-CT was able to increase the analgesic effect of the antidepressant drugs that reduce the uptake of 5-HT, suggesting that the joint administration of antidepressants and CT may be an interesting alternative in pain management.

Behavioral and analgesic effects induced by administration of nifedipine and nimodipine.

Evidence exists that calcium antagonists can have effects on neural function. The aim of this work is to analyze the effect of two dihydropyridines, nifedipine and nimodipine, administered for 11 days on the behavior and pain sensitivity of rats. Nociception was tested using the tail electric stimulation test, and behavior parameters using a holeboard. Our results show that chronic administration of nifedipine or nimodipine induces analgesia that can be evaluated by tail withdrawal. However, neither the vocalization nor the vocalization after discharge were modified, so the analgesia may be mediated by spinal mechanisms. Rats treated with nifedipine or nimodipine exhibited a dose-dependent tendency to avoid the center of the field without modification of other parameters, suggesting an increased emotivity in the rats. This conclusion is supported by the fact that anxiogenic or anxiolytic drugs modify the pattern of locomotion without significant changes in other parameters related with the motility. The results from this study suggest the view of a complex mechanism of action underlying nifedipine- and nimodipine-mediated behavioral effects.

Age-related changes in the antinociception induced by taurine in mice.

Taurine is a nonessential amino acid that is of medical interest for the nutrition of infants. Taurine has been found in the central nervous system of rodents and humans, and among its potential therapeutic uses, it is interesting to remark its analgesic actions. It is also well known that concentration levels during the fetal and prenatal periods are higher than in adulthood. The data obtained so far indicate that taurine is involved in the development process of the brain and possibly other organs. The taurine levels in old age are still unknown, but it is presumed that they will be different from those of younger animals. Data about age-related alterations and functional modifications of this and other amino acids are still scarce. The aim of the present work was to study the antinociceptive effect of taurine and its relationship with aging in mice. No differences were found between prepubertal and young adult animals; on the contrary, old animals showed significantly reduced sensitivity to the antinociception induced by taurine; in fact, at the tested doses, taurine did not induce antinociception in this group of mice. The mechanism underlying this effect has not been clarified because there are several mechanisms and neurotransmitter systems involved in the antinociception induced by taurine.

Pain relief by applying transcutaneous electrical nerve stimulation (TENS) during unsedated colonoscopy: a randomized double-blind placebo-controlled trial.

Transcutaneous electrical nerve stimulation (TENS) is a noninvasive alternative to traditional pain treatments. TENS has been studied in the past as a pain reduction modality in colonoscopy with limited success. Reviews and meta-analysis have shown that the inconclusive results of TENS may be due to the lack of randomized controlled trials and the difficulty in defining precise output parameters. The objective of this double-blind randomized placebo-controlled trial was to investigate the pain-relieving effect of a new application of TENS in unsedated screening colonoscopy. Ninety patients undergoing unsedated screening colonoscopy were randomly allocated to one of three groups: a control group (n=30), a group to receive active TENS (n=30), or a group to receive placebo TENS (n=30). A visual analogue scale (VAS) and a five-point Likert scale were used to assess pain 5 min into the procedure and at the end of the procedure. The patient's bloating sensation during colonoscopy and the effect on the duration of the procedure were also evaluated. Throughout the procedure, the active TENS group experienced a VAS pain score reduction ≥50% compared to the placebo TENS group (P<0.001) and the control group (P<0.001). On the five-point Likert scale, there was also a significant reduction in pain score in the active TENS group compared to the placebo TENS and control groups (P=0.009). No significant differences were found between the study groups as to the bloating sensation and the duration of the procedure. We conclude that TENS can be used as a pain relief therapy in unsedated screening colonoscopy.

«Primum interpretare». Para qué sirve un estudio clínico / «Primum interpretare». What's the point of a clinical assay?

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¿Qué respuesta fisiológica desencadena la aplicación de la técnica de estimulación nerviosa eléctrica transcutánea? / Which physiological response triggers the application of the transcutaneous electrical nerve stimulation technique?

Objetivo. Revisar qué efectos fisiológicos tiene la aplicación de la técnica de estimulación nerviosa eléctrica transcutánea (TENS) sobre los pacientes, de modo que pueda servir de orientación para su correcta aplicación en la práctica clínica. La técnica TENS consiste en la aplicación de corriente eléctrica pulsada, tradicionalmente empleada con finalidad analgésica. A la hora de su utilización, los diferentes parámetros de programación del TENS deben ajustarse teniendo en cuenta que las diferentes posibilidades de programación van a activar diferentes mecanismos fisiológicos. En los últimos tiempos, se han venido realizando importantes estudios con animales y en sujetos sanos, con el fin de dilucidar qué efectos fisiológicos son los que se producen en el organismo al aplicarse TENS. Material y métodos. Se llevó a cabo una revisión exhaustiva de la literatura científica publicada sobre la utilización de la técnica TENS y sus efectos fisiológicos. Los estudios relevantes fueron identificados a través de una búsqueda en las diversas bases de datos, así como de libros de referencia en la materia, procedentes de la Biblioteca de la Universidad CEU-Cardenal Herrera de Valencia. Resultados. Se localizaron 97 referencias que cumplieron con los criterios de inclusión. Conclusiones. El TENS produce su efecto analgésico por la activación de las aferencias de los tejidos profundos por estimulación de las fibras aferentes primarias de gran diámetro ABeta. Los mecanismos de acción fisiológicos del TENS de alta y baja frecuencia son distintos, aunque ambos se producen a nivel periférico, espinal y supraespinal, y se basan primordialmente en la activación de distintos receptores opioides. Con la combinación de parámetros adecuada, el TENS reduce el dolor desde el primer minuto de aplicación. Respecto a la duración del efecto analgésico tras una sesión de tratamiento, se ha demostrado la importancia de emplear intensidades elevadas para conseguir una mayor duración del efecto postsesión. La aplicación repetida diariamente de TENS con los mismos parámetros produce el desarrollo de tolerancia. Aunque se ha especulado respecto a un efecto vascular de la aplicación de TENS, éste sólo tiene efecto sobre la circulación periférica aplicado a una intensidad suficiente para conseguir contracciones musculares importantes; en todo caso, el efecto es local sobre la zona de aplicación. La aplicación de TENS puede influir positivamente en la actividad muscular de pacientes con déficits motores en accidentes cerebrovasculares y otros desórdenes neurológicos (AU)

Purpose. To analyze the physiological effects of the application of the transcutaneous electrical nerve stimulation (TENS) technique on patients, to provide guidance for successful implementation in clinical practice. TENS technique involves the application of a pulsed electric current, traditionally used for pain control. Different TENS programming parameters should be adjusted, taking into account that the different programming options will activate various physiological mechanisms. Extensive studies in animals and in healthy subjects have been conducted recently, in order to elucidate the physiological effects produced in the body when TENS is applied. Material and methods. We conducted a comprehensive review of published scientific literature on the use of the TENS technique and its physiological effects. Relevant trials were identified through a search of various databases and reference books on the subject, from the Library of the CEU-Cardenal Herrera University of Valencia. Results. We found 97 references that met the inclusion criteria. Conclusions. TENS produces its analgesic effect by activation of afferents of deep tissues by stimulation of primary ABeta large diameter afferent fibers. The physiological mechanisms of action of TENS at low and high frequency are different, although both occur at peripheral, spinal and supraspinal level, and are based primarily on the activation of different opioid receptors. With the proper combination of parameters, TENS reduces pain from the first minute of application. Regarding the duration of analgesic effect after a treatment session, it is known the importance of using higher intensities for greater duration of post-session effect. The daily repeated application of TENS with the same parameters will lead to the development of tolerance. Although there has been speculation about a vascular effect of the application of TENS, it only has an effect on peripheral circulation when applied at intensity sufficient to achieve significant muscle contractions; in any case the effect is reduced in the area of application. The application of TENS can positively influence muscle activity in patients with motor deficits in stroke and other neurological disorders (AU)