Extract of Glycyrrhiza glabra root attenuates nociception in experimental pain models: the role of BKCa channels / Extracto de raíz de Glycyrrhiza glabra atenúa la nocicepción en modelos experimentales de dolor: el rol de los canales BKCa

Abstract: The aim of this study was to evaluate the functional interaction of Glycyrrhiza glabra root extract (GGRE) on the large conductance Ca 2+ - activated K + (BKCa) channels expressed in the peripheral nervo us system by using nociception and inflammation models in rodents in vivo . Besides toxicity studies and open field tests, nociception and inflammation tests were performed on rodents. Different doses of GGRE were given orally to rats and mice. Naloxone, in domethacin, morphine, NS1619 and iberiotoxin (IbTX) were administered. GGRE had both anti - nociceptive and anti - inflammatory activity in rats and mice. GGRE exhibited an analgesic effect by decreasing the time - course of the pain threshold or reaction time i n some nociceptive tests. Furthermore, GGRE reduced level of pro - inflammatory cytokines, including TNF - α and IL - 1ß. As a conclusion, GGRE can alleviate the pain sensation of the afferent nerves and can reduce inflammation and associated pain by activating B KCa channels and reducing the levels of TNF - α, IL1ß

Resumen: El objetivo de este estudio fue evaluar la interacción funcional del extracto de raíz de Glycyrr hiza glabra (GGRE) en los canales de K + (BKCa) activados por Ca 2+ de gran conductancia expresados en el sistema nervioso periférico mediante el uso de modelos de nocicepción e inflamación en roedores in vivo . Además de los estudios de toxicidad y las prueb as de campo abierto, se realizaron pruebas de nocicepción e inflamación en roedores. Se administraron por vía oral diferentes dosis de GGRE a ratas y ratones. Se administraron naloxona, indometacina, morfina, NS1619 e iberiotoxina (IbTX). GGRE tenía activi dad tanto antinociceptiva como antiinflamatoria en ratas y ratones. GGRE mostró un efecto analgésico al disminuir la evolución temporal del umbral del dolor o el tiempo de reacción en algunas pruebas nociceptivas. Además, GGRE redujo el nivel de citocinas proinflamatorias, incluidas TNF - α e IL - 1ß. Como conclusión, GGRE puede aliviar la sensación de dolor de los nervios aferentes y puede reducir la inflamación y el dolor asociado activando los canales BKCa y reduciendo los niveles de TNF - α, IL1ß.

Analgesia Nociception Index: assessment of acute postoperative pain / Índice de Analgesia/Nocicepção: avaliação da dor aguda pós-operatória

Abstract Background and objectives Patient self-rating based scales such as Numerical Rating Scale, Visual Analog Scale that is used for postoperative pain assessment may be problematic in geriatric or critically ill patients with communication problems. A method capable of the assessment of pain in objective manner has been searched for years. Analgesia nociception index, which is based on electrocardiographic data reflecting parasympathetic activity, has been proposed for this. In this study we aimed to investigate the effectiveness of analgesia nociception index as a tool for acute postoperative pain assessment. Our hypothesis was that analgesia nociception index may have good correlation with Numerical Rating Scale values. Methods A total of 120 patients of American Society of Anesthesiologists (ASA) physical status I and II undergoing any surgical procedure under halogenated-based anesthesia with fentanyl or remifentanil were enrolled for the study. At the 15th minute of arrival to the Postoperative Care Unit the patients' pain was rated on a 0-10 point Numerical Rating Scale. The patients' heart rate, blood pressure, and analgesia nociception index scores were simultaneously measured at that time. The correlation between analgesia nociception index, heart rate, blood pressure and Numerical Rating Scale was examined. Results The study was completed with 107 patients, of which 46 were males (43%). Mean (SD) analgesia nociception index values were significantly higher in patients with initial Numerical Rating Scale ≤3, compared with Numerical Rating Scale >3 (69.1 [13.4] vs. 58.1 [12.9] respectively, p < 0.001). A significant negative linear relationship (r 2 = -0.312, p = 0.001) was observed between analgesia nociception index and Numerical Rating Scale. Conclusion Analgesia nociception index measurements at postoperative period after volatile agent and opioid-based anesthesia correlate well with subjective Numerical Rating Scale scores.

Resumo Justificativa e objetivo As escalas baseadas na autoavaliação de pacientes, como a Escala Visual Numérica e a Escala Visual Analógica, que são usadas para avaliar a dor pós-operatória podem ser problemáticas em pacientes geriátricos ou em estado crítico com problemas de comunicação. Portanto, um método capaz de avaliar a dor de maneira objetiva vem sendo pesquisado há anos. O índice de analgesia/nocicepção, baseado em dados eletrocardiográficos que refletem a atividade parassimpática, tem sido proposto para tal avaliação. Neste estudo, objetivamos investigar a eficácia do índice de analgesia/nocicepção como uma ferramenta para a avaliação da dor pós-operatória aguda. Nossa hipótese foi que o índice de analgesia/nocicepção pode ter boa correlação com os valores da Escala de Classificação Numérica. Métodos Um total de 120 pacientes com estado físico ASA I e II, submetidos a qualquer procedimento cirúrgico com o uso de anestésicos halogenados associados a fentanil ou remifentanil, foi incluído no estudo. No 15º minuto após a chegada à sala de recuperação pós-anestesia, a dor dos pacientes foi avaliada em uma escala numérica de 0-10 pontos. Os escores de frequência cardíaca, pressão arterial e o índice de analgesia/nocicepção dos pacientes foram medidos simultaneamente naquele momento. A correlação entre o índice de analgesia/nocicepção, frequência cardíaca, pressão arterial e a Escala Visual Numérica foi avaliada. Resultados O estudo foi concluído com 107 pacientes, dos quais 46 eram do sexo masculino (43%). Os valores da média (DP) do índice de analgesia/nocicepção foram significativamente maiores nos pacientes com valor inicial na Escala Visual Numérica ≤ 3, em comparação com valor na mesma escala > 3 (69,1 [13,4] vs. 58,1 [12,9], respectivamente, p < 0,001). Uma relação linear negativa significativa (r2 = -0,312, p = 0,001) foi observada entre o índice de analgesia/nocicepção e a Escala Visual Numérica. Conclusão As mensurações do índice de analgesia/nocicepção no pós-operatório após anestesia com agentes halogenados e opioides mostraram boa correlação com os escores subjetivos da Escala Visual Numérica.

Essential oil of Pterodon polygalaeflorus Benth attenuates nociception in mice

Essential oils (EO) are volatile liquids responsible for the aroma of plants. Pterodon polygalaeflorus seeds have received widespread use in folk medicine for the treatment of inflammatory diseases. For this reason and because Pterodon polygalaeflorus seeds have great EO content, which is frequently pharmacologically active, the present study aimed to evaluate the antinociceptive effect of EO from Pterodon polygalaeflorus (EOPPgfl) and its acute toxic effects. The EEOPPgfl sample, which was extracted by steam distillation of the seeds, had a yield of 2.4% of the seeds weight and had, as major constituents, beta-elemene (48.19%), trans-caryophyllene (19.51%), and epi-bicyclosesquiphellandrene (12.24%). The EOPPgfl sample showed mild acute toxicity and its calculated median lethal dose (LD50) was 3.38 g/kg. EOPPgfl (20-60 mg/kg) showed antinociceptive activity as evidenced by several tests and inhibited writhing induced by acetic acid. The maximum effect was obtained with the 30 mg/kg dose and at 60 min after its administration. EOPPgfl also decreased formalin-induced nociception, as verified by the inhibition of the first and second phase of the formalin test. At 30 mg/kg, EOPPgfl also decreased thermally stimulated nociception. Nociception may be related to inflammatory and antiedematogenic activity and at doses ranging 10-100 mg/kg, EOPPgfl blocked dextran- and carrageenan-induced edema. The results demonstrated that EOPPgfl presented, at doses approximately 100 times smaller than LD50, an antinociceptive effect that probably was due to anti-inflammatory activities.

Central release of nitric oxide mediates antinociception induced by aerobic exercise

Nitric oxide (NO) is a soluble gas that participates in important functions of the central nervous system, such as cognitive function, maintenance of synaptic plasticity for the control of sleep, appetite, body temperature, neurosecretion, and antinociception. Furthermore, during exercise large amounts of NO are released that contribute to maintaining body homeostasis. Besides NO production, physical exercise has been shown to induce antinociception. Thus, the present study aimed to investigate the central involvement of NO in exercise-induced antinociception. In both mechanical and thermal nociceptive tests, central [intrathecal (it) and intracerebroventricular (icv)] pretreatment with inhibitors of the NO/cGMP/KATP pathway (L-NOArg, ODQ, and glybenclamide) prevented the antinociceptive effect induced by aerobic exercise (AE). Furthermore, pretreatment (it, icv) with specific NO synthase inhibitors (L-NIO, aminoguanidine, and L-NPA) also prevented this effect. Supporting the hypothesis of the central involvement of NO in exercise-induced antinociception, nitrite levels in the cerebrospinal fluid increased immediately after AE. Therefore, the present study suggests that, during exercise, the NO released centrally induced antinociception.

Effectiveness of hip muscle strengthening in patellofemoral pain syndrome patients: a systematic review

Introduction: Patellofemoral pain syndrome (PFPS) is characterized by anterior knee pain, which may limit the performance of functional activities. The influence of hip joint motion on the development of this syndrome has already been documented in the literature. In this regard, studies have investigated the effectiveness of hip muscle strengthening in patients with PFPS. Objectives: The aims of this systematic review were (1) to summarize the literature related to the effects of hip muscle strengthening on pain intensity, muscle strength, and function in individuals with PFPS and (2) to evaluate the methodological quality of the selected studies. Method: A search for randomized controlled clinical trials was conducted using the following databases: Google Scholar, MEDLINE, PEDro, LILACS, and SciELO. The selected studies had to distinguish the effects of hip muscle strengthening in a group of patients with PFPS, as compared to non-intervention or other kinds of intervention, and had to investigate the following outcomes: pain, muscle strength, and function. The methodological quality of the selected studies was analyzed by means of the PEDro scale. Results: Seven studies were selected. These studies demonstrated that hip muscle strengthening was effective in reducing pain. However, the studies disagreed regarding the treatments' ability to improve muscle strength. Improvement in functional capabilities after hip muscle strengthening was found in five studies. Conclusion: Hip muscle strengthening is effective in reducing the intensity of pain and improving functional capabilities in patients with PFPS, despite the lack of evidence for its ability to increase muscle strength. .

Tiopental altera a resposta nociceptiva de ratos jovens em longo prazo / Thiopental alters long term nociceptive response of young rats

The objective of this study was to evaluate the long term nociceptive response determined by use of two general anesthetics, one intravenous and the other inhalatory, in young animals. In the first experiment, the animals of 21 days of age were divided into control (saline) and thiopental (35 mg/kg, i.p.) groups. In the second experiment, rats of the same age were divided in two groups ­ halothane (2%) and control. In experiment 1, there was difference between groups ­ reduction of tail-flick latency in the group thiopental (P< 0.05). In experiment 2, there were no differences between groups or interaction between time versus group (F(1,19)=0.11 for groups, P>0.05; F(1,19)=0.032 for the interaction, P>0.05). The results obtained in this study showed that halothane did not alter the nociceptive response in young animals. However, the thiopental induced hyperalgesic response in rats. (AU)

O objetivo desse estudo foi avaliar a resposta nociceptiva a longo prazo relacionada ao uso de dois anestésicos gerais ­ um intravenoso e outro inalatório, em animais jovens. No primeiro experimento, os animais de 21 dias de idade foram divididos nos grupos controle (solução salina) e tiopental sódico (35 mg/kg, i.p.). No segundo experimento, animais de mesma idade foram divididos em dois grupos ­ halotano (2%) e controle. No Experimento 1, houve redução da latência de retirada da cauda no grupo tiopental (P<0,05). No Experimento 2, não houve diferença entre os grupos ou interação entre grupo x tempo (F(1,19)=0,11 para grupos, P>0,05; F(1,19)=0,032 para a interação, P>0,05). Os resultados obtidos nesse estudo demonstraram que o halotano não altera a resposta nociceptiva em animais jovens. Entretanto, o tiopental induziu resposta hiperalgésica nestes ratos.(AU)

Participation of cannabinoid receptors in peripheral nociception induced by some NSAIDs

Nonsteroidal anti-inflammatory drugs (NSAIDs) have been used extensively to control inflammatory pain. Several peripheral antinociceptive mechanisms have been described, such as opioid system and NO/cGMP/KATP pathway activation. There is evidence that the cannabinoid system can also contribute to the in vivo pharmacological effects of ibuprofen and indomethacin. However, there is no evidence of the involvement of the endocannabinoid system in the peripheral antinociception induced by NSAIDs. Thus, the aim of this study was to investigate the participation of the endocannabinoid system in the peripheral antinociceptive effect of NSAIDs. All experiments were performed on male Wistar rats (160-200 g; N = 4 per group). Hyperalgesia was induced by a subcutaneous intraplantar (ipl) injection of prostaglandin E2 (PGE2, 2 μg/paw) in the rat’s hindpaw and measured by the paw pressure test 3 h after injection. The weight in grams required to elicit a nociceptive response, paw flexion, was determined as the nociceptive threshold. The hyperalgesia was calculated as the difference between the measurements made before and after PGE2, which induced hyperalgesia (mean = 83.3 ± 4.505 g). AM-251 (80 μg/paw) and AM-630 (100 μg/paw) were used as CB1 and CB2 cannabinoid receptor antagonists, respectively. Ipl injection of 40 μg dipyrone (mean = 5.825 ± 2.842 g), 20 μg diclofenac (mean = 4.825 ± 3.850 g) and 40 μg indomethacin (mean = 6.650 ± 3.611 g) elicited a local peripheral antinociceptive effect. This effect was not antagonized by ipl CB1 cannabinoid antagonist to dipyrone (mean = 5.00 ± 0.9815 g), diclofenac (mean = 2.50 ± 0.8337 g) and indomethacin (mean = 6.650 ± 4.069 g) or CB2 cannabinoid antagonist to dipyrone (mean = 1.050 ± 6.436 g), diclofenac (mean = 6.675 ± 1.368 g) and indomethacin (mean = 2.85 ± 5.01 g). Thus, cannabinoid receptors do not seem to be involved in the peripheral antinociceptive mechanism of the NSAIDs dipyrone, diclofenac and indomethacin.

Participation of the NO/cGMP/K+ATP pathway in the antinociception induced by Walker tumor bearing in rats

Implantation of Walker 256 tumor decreases acute systemic inflammation in rats. Inflammatory hyperalgesia is one of the most important events of acute inflammation. The L-arginine/NO/cGMP/K+ATP pathway has been proposed as the mechanism of peripheral antinociception mediated by several drugs and physical exercise. The objective of this study was to investigate a possible involvement of the NO/cGMP/K+ATP pathway in antinociception induced in Walker 256 tumor-bearing male Wistar rats (180-220 g). The groups consisted of 5-6 animals. Mechanical inflammatory hypernociception was evaluated using an electronic version of the von Frey test. Walker tumor (4th and 7th day post-implantation) reduced prostaglandin E2- (PGE2, 400 ng/paw; 50 µL; intraplantar injection) and carrageenan-induced hypernociception (500 µg/paw; 100 µL; intraplantar injection). Walker tumor-induced analgesia was reversed (99.3% for carrageenan and 77.2% for PGE2) by a selective inhibitor of nitric oxide synthase (L-NAME; 90 mg/kg, ip) and L-arginine (200 mg/kg, ip), which prevented (80% for carrageenan and 65% for PGE2) the effect of L-NAME. Treatment with the soluble guanylyl cyclase inhibitor ODQ (100% for carrageenan and 95% for PGE2; 8 µg/paw) and the ATP-sensitive K+ channel (KATP) blocker glibenclamide (87.5% for carrageenan and 100% for PGE2; 160 µg/paw) reversed the antinociceptive effect of tumor bearing in a statistically significant manner (P < 0.05). The present study confirmed an intrinsic peripheral antinociceptive effect of Walker tumor bearing in rats. This antinociceptive effect seemed to be mediated by activation of the NO/cGMP pathway followed by the opening of KATP channels.

Contrasting effects of nitric oxide and corticotropin- releasing factor within the dorsal periaqueductal gray on defensive behavior and nociception in mice

The anxiogenic and antinociceptive effects produced by glutamate N-methyl-D-aspartate receptor activation within the dorsal periaqueductal gray (dPAG) matter have been related to nitric oxide (NO) production, since injection of NO synthase (NOS) inhibitors reverses these effects. dPAG corticotropin-releasing factor receptor (CRFr) activation also induces anxiety-like behavior and antinociception, which, in turn, are selectively blocked by local infusion of the CRF type 1 receptor (CRFr1) antagonist, NBI 27914 [5-chloro-4-(N-(cyclopropyl)methyl-N-propylamino)-2-methyl-6-(2,4,6-trichlorophenyl)aminopyridine]. Here, we determined whether i) the blockade of the dPAG by CRFr1 attenuates the anxiogenic/antinociceptive effects induced by local infusion of the NO donor, NOC-9 [6-(2-hydroxy-1-methyl-2-nitrosohydrazino)-N-methyl-1-hexanamine], and ii) the anxiogenic/antinociceptive effects induced by intra-dPAG CRF are prevented by local infusion of Nω-propyl-L-arginine (NPLA), a neuronal NOS inhibitor, in mice. Male Swiss mice (12 weeks old, 25-35 g, N = 8-14/group) were stereotaxically implanted with a 7-mm cannula aimed at the dPAG. Intra-dPAG NOC-9 (75 nmol) produced defensive-like behavior (jumping and running) and antinociception (assessed by the formalin test). Both effects were reversed by prior local infusion of NBI 27914 (2 nmol). Conversely, intra-dPAG NPLA (0.4 nmol) did not modify the anxiogenic/antinociceptive effects of CRF (150 pmol). These results suggest that CRFr1 plays an important role in the defensive behavior and antinociception produced by NO within the dPAG. In contrast, the anxiogenic and antinociceptive effects produced by intra-dPAG CRF are not related to NO synthesis in this limbic midbrain structure.

Sertraline inhibits formalin-induced nociception and cardiovascular responses

The objective of the present study was to determine the antihyperalgesic effect of sertraline, measured indirectly by the changes of sciatic afferent nerve activity, and its effects on cardiorespiratory parameters, using the model of formalin-induced inflammatory nociception in anesthetized rats. Serum serotonin (5-HT) levels were measured in order to test their correlation with the analgesic effect. Male Wistar rats (250-300 g) were divided into 4 groups (N = 8/per group): sertraline-treated group (Sert + Saline (Sal) and Sert + Formalin (Form); 3 mg·kg-1·day-1, ip, for 7 days) and saline-treated group (Sal + Sal and Sal + Form). The rats were injected with 5 percent (50 µL) formalin or saline into the right hind paw. Sciatic nerve activity was recorded using a silver electrode connected to a NeuroLog apparatus, and cardiopulmonary parameters (mean arterial pressure, heart rate and respiratory frequency), assessed after arterial cannulation and tracheotomy, were monitored using a Data Acquisition System. Blood samples were collected from the animals and serum 5-HT levels were determined by ELISA. Formalin injection induced the following changes: sciatic afferent nerve activity (+50.8 ± 14.7 percent), mean arterial pressure (+1.4 ± 3 mmHg), heart rate (+13 ± 6.8 bpm), respiratory frequency (+4.6 ± 5 cpm) and serum 5-HT increased to 1162 ± 124.6 ng/mL. Treatment with sertraline significantly reduced all these parameters (respectively: +19.8 ± 6.9 percent, -3.3 ± 2 mmHg, -13.1 ± 10.8 bpm, -9.8 ± 5.7 cpm) and serum 5-HT level dropped to 634 ± 69 ng/mL (P < 0.05). These results suggest that sertraline plays an analgesic role in formalin-induced nociception probably through a serotonergic mechanism.