Activation of C-fiber nociceptors by low-power diode laser / Ativação por laser de diodo de baixa potência de nociceptores relacionados a fibras C

ABSTRACT Objective The evaluation of selective activation of C-fibers to record evoked potentials using the association of low-power diode laser (810 nm), tiny-area stimulation and skin-blackening. Method Laser-evoked potentials (LEPs) were obtained from 20 healthy young subjects. An aluminum plate with one thin hole was attached to the laser probe to provide tiny-area stimulation of the hand dorsum and the stimulated area was covered with black ink. Results The mean intensity used for eliciting the ultra-late laser-evoked potential (ULEP) was 70 ± 32 mW. All subjects showed a clear biphasic potential that comprised a negative peak (806 ± 61 ms) and a positive deflection (1033 ± 60 ms), corresponding to the ULEP related to C-fiber activation. Conclusion C-fiber-evoked responses can be obtained using a very low-power diode laser when stimulation is applied to tiny areas of darkened skin. This strategy offers a non-invasive and easy methodology that minimizes damage to the tissue.

RESUMO Objetivo Avaliação da ativação de fibras C para o registro de potenciais evocados utilizando-se laser de baixa potência, áreas pequenas de estimulação e escurecimento da pele. Método Potenciais evocados foram obtidos de 20 sujeitos. Uma placa de alumínio com uma pequena abertura foi acoplada à ponteira do laser para estimular área escurecida do dorso da mão. Resultados A intensidade média utilizada para estimulação foi de 70 ± 32 mW. Todos os sujeitos apresentaram respostas claras compreendendo dois picos um negativo (806 ± 61 ms) seguido por outro positivo (1033 ± 60 ms), correspondendo ao potencial evocado tardio por estimulação de fibras C. Conclusão Respostas de fibras C podem ser obtidas utilizando-se laser de baixa potência quando a estimulação é aplicada a pequenas áreas de pele escurecida. Esta estratégia oferece uma metodologia não invasiva que minimiza danos teciduais.

Antagonistas serotoninérgico e noradrenérgico por via subaracnoidea aumentam a resposta álgica em ratos / Subarachnoid serotonergic and noradrenergic antagonists increase the pain response in rats

JUSTIFICATIVA E OBJETIVOS: Há evidências de que a passagem de informações nociceptivas pelo corno posterior da medula espinhal (CPME) seguindo para níveis rostrais do sistema nervoso central sofre profundas influências excitatórias e inibitórias. A presente pesquisa teve como objetivo comparar os efeitos da metissergida, da fentolamina e da fentolamina associada à metissergida, administrados por via subaracnoidea, sobre as fases I, intermediária e II do teste da formalina modificado em ratos. MÉTODO: Foram utilizados 28 ratos Wistar machos, distribuídos aleatoriamente em quatro grupos (n = 7) para receber solução salina (GC), fentolamina (GF), metissergida (GM) ou fentolamina associada à metissergida (GFM) por via subaracnoidea. A dor foi induzida pela administração de formalina na região dorsal da pata posterior direita. O teste foi dividido em três fases; fase I, intermediária e fase II. A análise estatística dos resultados foi realizada utilizando o programa SPSS (Statistical Package for Social Sciences), adotando o nível de significância de 5 por cento. RESULTADOS: Na fase intermediária, o número de elevações da pata foi significativamente maior nos grupos GF, GM e GFM quando comparados com o grupo GC. CONCLUSÕES: Os resultados sugerem a existência de efeito noradrenérgico e serotoninérgico no sistema inibitório descendente da dor aguda, com a possibilidade de emprego de agonistas serotoninérgicos e α1-adrenérgicos para controle da dor aguda.

BACKGROUND AND OBJECTIVES: There is evidence that the passage of nociceptive information through the posterior horn of the spinal cord (PHSC) on its way to rostral levels of the central nervous system undergoes profound excitatory and inhibitory influences. The objective of the present study was to compare the effects of the subarachnoid administration of methysergide, phentolamine, and phentolamine associated with methysergide on phases I, intermediate, and II of the modified phormaline test in rats. METHODS: Twenty-eight male Wistar rats distributed randomly in four groups (n = 7) to received subarachnoid saline solution (GC), phentolamine (GF), methysergide (GM), or phentolamine associated with methysergide (GFM). Pain was induced by the administration of phormaline in the dorsal region of the right hind paw. The test was divided in three phases: phase I, intermediate, and phase II. Statistical analysis of the results was performed using the software SPSS (Statistical Package for Social Sciences), adopting a level of significance of 5 percent. RESULTS: In the intermediate phase the number of paw elevations was significantly higher in GF, GM, and GFM groups when compared to the GC group. CONCLUSIONS: The results suggest the existence of a noradrenergic and serotonergic effect in the inhibitory descending system of acute pain, with the possibility of using serotonergic and α1-adrenergic antagonists to control acute pain.

JUSTIFICATIVA Y OBJETIVOS: Existen evidencias de que el paso de informaciones nociceptivas por el cuerno posterior de la médula espinal (CPME), y que continúa hacia niveles rostrales del sistema nervioso central, sufre profundas influencias excitatorias e inhibitorias. La presente investigación quiso comparar los efectos de la metisergida, de la fentolamina y de la fentolamina asociada a la metisergida, administrados por vía subaracnoidea, sobre las fases I, intermedia y II del test de la formalina modificado en ratones. MÉTODO: Fueron utilizados en el experimento, 28 ratones Wistar machos, distribuidos aleatoriamente en cuatro grupos (n = 7), para recibir una solución salina (GC), fentolamina (GF), metisergida (GM) o fentolamina asociada a la metisergida ((GFM). El dolor fue inducido por la administración de formalina en la región dorsal de la pata posterior derecha. El test fue dividido en tres fases: fase I, intermedia y fase II. El análisis estadístico de los resultados fue hecho utilizando el programa SPSS (Statistical Package for Social Sciences), [Paquete Estadístico para las Ciencias Sociales], adoptando el nivel de significancia de un 5 por ciento. RESULTADOS: En la fase intermedia, el número de elevaciones de la pata fue significativamente mayor en los grupos GF, GM y GFM cuando se comparó con el grupo GC. CONCLUSIONES: Los resultados nos sugieren la existencia de un efecto noradrenérgico y serotoninérgico en el sistema inhibitorio descendiente del dolor agudo, con la posibilidad del uso de agonistas serotoninérgicos y α1-adrenérgicos para el control del dolor agudo.

Streptozotocin-induced mechanical hypernociception is not dependent on hyperglycemia

Since streptozotocin (STZ)-induced diabetes is a widely used model of painful diabetic neuropathy, the aim of the present study was to design a rational protocol to investigate whether the development of mechanical hypernociception induced by STZ depends exclusively on hyperglycemia. Male Wistar rats (180-200 g; N = 6-7 per group) received a single intravenous injection of STZ at three different doses (10, 20, or 40 mg/kg). Only the higher dose (40 mg/kg) induced a significant increase in blood glucose levels, glucose tolerance and deficiency in weight gain. However, all STZ-treated rats (hyperglycemic or not) developed persistent (for at least 20 days) and indistinguishable bilateral mechanical hypernociception that was not prevented by daily insulin treatment (2 IU twice a day, sc). Systemic morphine (2 mg/kg) but not local (intraplantar) morphine treatment (8 µg/paw) significantly inhibited the mechanical hypernociception induced by STZ (10 or 40 mg/kg). In addition, intraplantar injection of STZ at doses that did not cause hyperglycemia (30, 100 or 300 µg/paw) induced ipsilateral mechanical hypernociception for at least 8 h that was inhibited by local and systemic morphine treatment (8 µg/paw or 2 mg/kg, respectively), but not by dexamethasone (1 mg/kg, sc). The results of this study demonstrate that systemic administration of STZ induces mechanical hypernociception that does not depend on hyperglycemia and intraplantar STZ induces mechanical sensitization of primary sensory neurons responsive to local morphine treatment.

Antinociception synergy between the peripheral and spinal sites of the heme oxygenase-carbon monoxide pathway

We have shown that the peripheral and spinal cord heme oxygenase (HO)-carbon monoxide (CO)-soluble guanylate cyclase-cGMP pathways play an important role in antinociception in the rat experimental formalin model. Our objective was to determine if there is synergism between peripheral (paw) and spinal HO-CO pathways in nociception. Rats were handled and adapted to the experimental environment for a few days before the formalin test, in which 50 µL of a 1 percent formalin was injected subcutaneously into the dorsal surface of the right hind paw. The animals were then observed for 1 h and the frequency of flinching behavior was taken to represent the nociceptive response. Thirty minutes before the test, rats were pretreated with intrathecal injections of the HO inhibitor, zinc deuteroporphyrin 2,4-bis glycol (ZnDPBG) or heme-lysinate, which is a substrate of the HO pathway. The paw treatments took place 20 min before the test. Low doses of ZnDPBG did not increase nociception, while a low heme-lysinate dose did not change flinching behavior after paw or spinal injections. Combined subactive spinal (50 nmol) and peripheral (40 nmol) low doses of ZnDPBG induced hypernociception (increase of 80 percent in the first and 25 percent in the second phase flinching), whereas combined spinal-peripheral heme-lysinate (50 and 30 nmol) led to second phase antinociception (40 percent reduction in flinching). These findings suggest a synergy between the peripheral and spinal HO-CO pathways. Local activation of the HO system probably regulates the nociception initiation in peripheral tissue and participates in buffering the emerging nociceptive signals at the peripheral and spinal sites of action. In short, an antinociceptive synergy exists between peripheral and spinal HO pathways, which may reduce the doses required and side effects.

Effect of dexmedetomidine on hemodynamic changes in children undergoing laparoscopic surgery

Stress response to surgery is modulated by numerous factors, including magnitude of the injury, type of procedure and anesthetic technique. Dexmedetomidine, a highly selective alpha[2]-adrenergic agonist, increases perioperative hemodynamic stability in healthy patients but decreases arterial blood pressure and heart rate. Purpose: This study was designed to assess the hemodynamic effects to nociceptive stimuli in children submitted to laparoscopic surgery under balanced anesthesia with sevoflurane and dexmedetomidine. Randomized, double-blind and placebo-controlled study including thirty children submitted to laparoscopic surgery. Patients were allocated to three equal groups [n=10]: [1] Low-dose DEX group: infusion of 0.5 micro g.kg[-1] over 10 minutes and maintenance dose of 0.5 beta g.kg.h[-1] [2] High-dose DEX group: infusion of 1 micro g.kg[-1] over 10 minutes and maintenance dose of 0.5 micro g.kg.h[-1] as an adjuvant to inhaled sevoflurane anesthesia; [3] Placebo group: normal saline infusion at a similar rate and volume of the dexmedetomidine infusion. Arterial blood pressure, heart rate, arterial oxygen saturation, end-tidal carbon dioxide tension as well as supplemental fentanyl requirement were observed. ANOVA, Chi-Square and kruskal-Wallis tests, with Bonferroni correction for inter-group comparison were used for statistical analysis. During the strongest nociceptive stimuli [airway access and abdominal catheter placement], children receiving high dose dexmedetomidine showed a remarkable reduction in all hemodynamic variables, and supplemental fentanyl doses [P<0.01]. Combined use of dexmedetomidine with inhaled sevoflurane in pediatric patients submitted to laparoscopic surgery, efficiently blocks the hemodynamic responses to nociceptive stimuli and surgical trauma due to suppression of sympathetic overactivity

Formalin assay parameters differ in confirming the antinociceptive mechanism of domperidone in mice.

Domperidone, a prokinetic drug with minimal extrapyramidal side-effects was investigated for its antinociceptive response in mice using formalin assay procedure. Two parameters namely the pain score and the time spent by the animal in licking/biting the formalin injected paw were considered. Domperidone (1, 2.5 or 5 mg/kg; ip) injected 15 min prior to formalin effectively reduced the pain score bringing it to zero at the 15th minute and was also effective till 30 min but to a lesser degree. This effect of domperidone (2.5 mg/kg) was significantly attenuated in naloxone pretreated mice indicating a partial role for opioid pathways. In the other parameter i.e. time spent in licking/biting, domperidone in all the doses employed failed to modify significantly the same by the animal in the early phase. In contrast, a dose related inhibition of the time spent was recorded in the late phase. Besides, a trend towards the enhancement of the inhibitory effect of domperidone (2.5 mg/kg) in the late phase was noticed in naloxone pretreated mice. Possibly, the peripheral analgesic mechanisms may play a role in this response since the late phase was considered akin to inflammation. The results confirm the antinociceptive effect of domperidone and suggest that caution be exercised while selecting the parameters when formalin assay is employed.

Anti-nociceptive effect of synthesized di-hydroxy flavones: possible mechanism.

Renewed interest on the research on the flavonoids is gaining more importance. Earlier literature on flavonoids indicated a significant anti-nociceptive action for flavones and mono-substituted flavones. However, they exhibited a ceiling effect. The present study was undertaken by new synthesizing six disubstituted flavones (DHFs) since poly substituted ones are expected to produce more potent effect. Their anti-nociceptive effect and the role of opioid involvement were studied using acetic acid induced abdominal constriction assay. All the six DHFs administered in elicited a dose related inhibition of abdominal constrictions indicating the presence of the anti-nociceptive response. However, these substances also showed a similar ceiling effect. Like other flavonoid substances, they also utilized opioid pathways. It is suggested that these newly synthesized DHFs can be included along with other flavonoids while attempting clinical trial for analgesic use.

Involvement of calcium in pain and antinociception

Calcium ions are widely recognized to play a fundamental role in the regulation of several biological processes. Transient changes in cytoplasmic calcium ion concentration represent a key step for neurotransmitter release and the modulation of cell membrane excitability. Evidence has accumulated for the involvement of calcium ions also in nociception and antinociception, including the analgesic effects produced by opioids. The combination of opioids with drugs able to interfere with calcium ion functions in neurons has been pointed out as a useful alternative for safer clinical pain management. Alternatively, drugs that reduce the flux of calcium ions into neurons have been indicated as analgesic alternatives to opioids. This article reviews the manners by which calcium ions penetrate cell membranes and the changes in these mechanisms caused by opioids and calcium antagonists regarding nociceptive and antinociceptive events

Involvement of dopamine D2 and 5-HT1A receptors in roxindole-induced antinociception.

Roxindole, a DA D2 receptor agonist (2-16 mg/kg) produced dose-dependent increase in percentage antinociception. The effect which was blocked by DA D2 antagonist (-)sulpiride (50 mg/kg) and 5-HT1A receptor antagonist (-) pindolol (5 mg/kg). Roxindole (4 and 8 mg/kg) reversed both naloxone (20 mg/kg)-induced hyperalgesia and reserpine (2 mg/kg)-induced hyperalgesia. This reversal was sensitive to blockade by both (-)sulpiride (50 mg/kg) and (-) pindolol (5 mg/kg). The present study suggests that roxindole-induced antinociception is mediated by postsynaptic DA D2 and 5-HT1A receptors.

Effect of aspartate and glutamate on nociception, catalepsy and core temperature in rats.

Effects of excitatory aminoacids (EAAs) aspartate (ASP) and glutamate (GLU) in a low (50 ng, i.c.) and high dose (20 micrograms, i.c.), were studied on nociception, catalepsy and rectal temperature in albino rats. Both ASP and GLU altered the tail flick reaction time to thermal stimulation in a dose dependent manner, increasing it with low doses and reduced with high doses. Naloxone (10 micrograms, ic) antagonized the anti-nociceptive effect of EAAs while ketamine (10 micrograms, ic)-a NMDA receptor antagonist antagonized the hyperalgesic effect. These EAAs also antagonized catalepsy induced by haloperidol, chlorpromazine, trifluoperazine and morphine. Both ASP and GLU produced a hyperthermic response in all animals, including those in which hypothermia was induced by reserpine. These EAAs produced a comparable central modulatory effects on nociception, catalepsy and core temperature.

Influence of low and high doses of naloxone on tonic pain and motor activity in rats.

Naloxone has been reported to affect pain and locomotor activity differently depending on the dose. The objective of the present investigation was to study the effects of low and high (6 micrograms and 3 mg/kg, s.c.) doses of naloxone (Nx) on formalin-induced pain (tonic pain) and spontaneous motor activity and any correlation between them. The experiments were conducted on adult male Wistar rats. Tonic pain and spontaneous motor activity were recorded by the formalin test and video monitoring respectively. An increase in spontaneous motor activity (locomotion, movements and distance) was observed following formalin injection as compared to basal activity (P < 0.05). Low dose of Nx reduced the pain intensity and also the spontaneous motor activity during the later phase (after 15 min of formalin injection) (P < 0.05). High dose of Nx on the other hand increased the pain intensity but still reduced motor activity (P < 0.05). Both doses of Nx initially produced hyperalgesia (5 min peak). The bidirectional effects of Nx on formalin pain were dissociated from the spontaneous motor behavior of rats. A direct correlation could not be established between pain intensity and spontaneous motor activity.

Uso de opioides en la analgesia epidural postoperatoria / Opioids use in epidural postoperative analgesia

En este estudio se hizo una revisión bibliográfica (1980 a 1994), en la cual se revisaron distintos opioides, los cuales son usados por vía epidural para el control del dolor en el periodo postoperatorio y con los cuales contamos en nuestro medio hospitalario. Se analizaron uno por uno de estos pioides, con el fin de corroborar que la vía epidural es una buena y segura opción para el control del dolor postoperatorio, y que todos los opioides en mayor o menor grado presentan efectos indeseables como son: náusea, vómito, prurito, sedación, llegada alguna de ellos a provocar depresión respiratoria con intervalos de apnea hasta de 30 segundos. La duración analgésica fue de 130 minutos hasta 20 horas dependiendo del tipo de opiáceo que se haya administrado. Debiéndose de seleccionar el pioide dependiendo del tipo de paciente, sitio de la cirugía, tipo de la cirugía y tiempo de estancia hospitalaria

Role of testosterone on pain threshold in rats.

Pain thresholds were recorded in rats by progressive increase in electrical stimulation to induce tail withdrawal, vocalisation and vocalisation after discharge. It was observed that castration resulted in significant reduction of pain threshold which however returned to normal level on substitution with testosterone therapy.

Oxido nítrico en la nocicepción / Nitric oxide and nociception

Las investigaciones en el campo del dolor y de la analgesia se están enfocando hacia los eventos celulares y moleculares subyacentes a los mecanismos de dolor crónico. En particular, mucha atención está recibiendo el óxido nítrico (ON), un nuevo tipo de neurotransmisor. El ON es un radical libre gaseoso e inestable que resulta de la oxidación de la L-arginina a L-citrulina en una reacción catalizada por la sintasa del óxido nítrico. El ON cumple un papel de molécula citotóxica de macrófagos activados y de relajante de músculo liso. Además de estas funciones, el ON actúa como neuromodulador y/o neurotransmisor en el sistema nervioso. Reportes recientes han comenzado a definir el papel del ON en los procesos nociceptivos a nivel de la médula espinal. Asociado a receptores sensibles al N-metil-D-aspartato (NMDA), parece estar involucrado en los mecanismos suyacentes de la hiperalgesia térmica, involucrado en la facilitación de reflejos térmicos. Es más, parece que la producción sostenida del On y la subsecuente activación de la guanilato ciclasa soluble en la médula espinal lumbar, son condiciones requeridas para el mantenimiento de la hiperalgesia térmica producida en modelos del dolor persistente. La inhibición de la sintasa del ON con nitro-L-arginina bloquea la tolerancia a la morfina en ratones. La nitro-L-arginina también es capaz de revertir lentamente tolerancia preexistente, además de reducir la dependencia y de revertir la dependencia a la droga previemente establecida. La acción del ON es selectivo para la tolerancia y dependencia a receptores del subtipo µ

Taurine modulates chemical nociception in mice

The effect of taurine on nociception was investigated in adult male Swiss mice using the formalin and acetic acid tests. Taurine (50-200 mg/kg) injected sc into the animals (N = 6 per group) 30 min before formalin injection into the right hind paw reduced formalin-induced early phase (0-5 min) licking activity by 30-42 per cent , but had no effect on the late phase (20-25 min) response. Writhing responses induced by acetic acid injected ip were also significantly inhibited by 49 per cent and 56 per cent by doses of 100 and 200 mg/kg taurine, respectively. In both tests taurine demonstrated antinociception which was significantly blocked by naloxone (1 mg/kg, sc, administered simultaneously with taurine). The naloxone-sensitive antinociceptive action of taurine was probably mediated via modulation of endogenous pain-regulatory systems that involve opioid peptides, neuropeptides like substance P and amino acids such as glutamate and aspartate

Neonatal treatment with naloxone causes permanent hyperalgesia in rats

The effect of treatment with naloxone early in life on pain responsiveness was studied in Wistar rats. Litters of six rats were divided equally into groups of 3 pups receiving daily naloxone (50 mg/kg, sc) and 3 pups receiving saline from the 3rd to 18th day of life. On days 30, 50, 70 and 90, one group of animals previously injected during suckling with naloxone (N = 21) and another with saline (N = 21) were submitted to the hot-plate test to measure the latency to paw licking. Other groups of rats also treated during suckling with naloxone (N = 13) and saline (N = 14) were assessed for the antinociceptive effect of morphine (10 mg/kg,sc). The naloxone group displayed a lower latency than the saline group in all test sessions and a diminished analgesic response to morphine. The results indicate that the use of naloxone (an antagonist opioid) during suckling, the brain growth spurt period, facilitates a long-lasting increased pain responsiveness and alters antialgesic mechanisms. In this respect, the opioid and non-opioid effects of naloxone on the ontogeny of neural systems should be taken into account

Urinary bladder serosal chemoreceptor induced cardio-respiratory responses: possible pathway.

There is limited experimental information about pain originating from the urinary bladder. In the present study application of 3-5 ml of 1% ammonium oxalate, 1% potassium chloride, 100m M citric acid, IM ammonium chloride, 1% oxalic acid, 0.5% sodium hydroxide, or 2 micrograms/ml bradykinin, to the serosal surface of the urinary bladder in anaesthetized dogs, resulted in an increase in heart rate, rise of both systolic and diastolic blood pressures and increase in respiratory rate and depth. These facilitatory cardio-respiratory responses were coupled with powerful contractions of the urinary bladder wall. By contrast, mucosal application of the chemicals did not bring about any significant change. The cardio-respiratory responses obtained were completely abolished on serosal application of procaine (1%), section of the hypogastric nerves or by spinalectomy at T8. Bilateral cervical vagotomy and pelvic nerve section did not modify the responses. However, the blood pressure responses were abolished by the administration of tolazoline hydrochloride, indicating a major role of sympathetics in this nociceptive reflex.