Efeitos da fotobiomodulação na atividade de nociceptores e na expressão de citocinas pró-inflamatórias após lesão do disco da articulação temporomandibular em ratos / Effects of Photobiomodulation on nociceptive activity and in the expression of inflammatory citokynes after injury of the Temporomandibular Joint disc after in rats

A dor na articulação temporomandibular (ATM) é comum na clínica, na forma de artralgia. Geralmente, é devido a distúrbios do disco articular, deslocamentos ou trauma. Nosso objetivo foi analisar os efeitos da fotobiomodulação (PBM) na atividade nociceptora e na expressão de substâncias pró-inflamatórias no disco da ATM após lesão unilateral em ratos. Foi realizada lesão no disco após acesso cirúrgico na ATM sob anestesia geral. 40 ratos foram divididos em 4 grupos (n = 10 cada): Grupo Op + PBM: Lesão cirúrgica do disco articular e PBM; Grupo SHAM: Falso operado +PBM; Grupo Op: lesão cirúrgica do disco articular; Grupo Naive: controle. Dez sessões foram realizadas com laser GaAs com comprimento de onda de 904 nm e densidade de energia 6J / cm2. Uma parte das amostras contendo tecidos moles articulares foram preparadas para determinação do conteúdo protéico por espectrofotometria da substância P (SP), receptor do potencial transiente vaniloide do subtipo-1 (TRPV-1) e peptídeo relacionado ao gene da calcitonina (CGRP), Interleucina 6 (IL-6), Interleucina 1 beta (IL1-) e Fator de Necrose Tumoral alfa (TNF-). Foi realizada análise de variância de duas vias com pós-teste de Tukey (p <0,050). Outra parte foi utilizada para análise histológica e histomorfometrica. Houve aumento da expressão das substâncias avaliadas após lesão e uma diminuição significante após PBM, quando comparado com os demais grupos. A análise histológica e histomorfométrica mostrou reparação com melhor organização tecidual no grupo Op + PBM O uso da PBM é eficaz na modulação da atividade nociceptora e nas expressões das citocinas pró-inflamatórias na ATM.

Pain in the temporomandibular joint (TMJ) is common in the clinic, in the form of arthralgia. It is usually due to joint disc disorders, dislocations, or trauma. Our objective was to analyze the effects of photobiomodulation (PBM) on nociceptor activity and on the expression of pro-inflammatory substances in the TMJ disc after unilateral injury in rats. Disc injury was performed after surgical access to the TMJ under general anesthesia. 40 rats were divided into 4 groups (n = 10 each): Group Op + PBM: Surgical lesion of the articular disc and PBM; SHAM group: False operated +PBM; Group Op: surgical lesion of the articular disk; Naive group: control. Ten sessions were performed with a GaAs laser with a wavelength of 904 nm and an energy density of 6J/cm2. A portion of the samples containing joint soft tissues were prepared for determination of protein content by spectrophotometry of substance P (SP), receptor transient vanilloid potential subtype-1 (TRPV-1) and calcitonin gene-related peptide (CGRP), Interleukin 6 (IL-6), Interleukin 1 beta (IL1-) and Tumor Necrosis Factor alpha (TNF-). Two-way analysis of variance with Tukey's post-test (p<0.050) was performed. Another part was used for histological and histomorphometric analysis. There was an increase in the expression of the evaluated substances after injury and a significant decrease after PBM, when compared to the other groups. Histological and histomorphometric analysis showed repair with better tissue organization in the Op + PBM group the use of PBM is effective in modulating nociceptor activity and expressions of pro-inflammatory cytokines in the TMJ.

La relevancia moral del dolor de animales de experimentación y de producción / The moral relevance of pain in experimental and production animals

RESUMEN: El aspecto emocional del dolor no solo es controvertido en aves, peces y roedores, sino también en los seres humanos autoconscientes. Cuando el dolor emocional, o la insatisfacción, es vista como un mal intrínseco, evitarla o, al menos, minimizarla es un deber moral directo. El objetivo de este artículo es mostrar que no solo los modelos animales mamíferos que se utilizan en experimentación -rata (Rattus norvegicus) y ratón (Mus musculus)- sienten dolor, como reconocen universalmente las instituciones que se ocupan del bienestar animal, sino también los peces de laboratorio (Danio rerio) y los de producción (Salmo salar), y que este hecho es moralmente relevante desde el punto de vista de todas las concepciones de la moral que suelen enfrentarse en los debates morales públicos y académicos. En consecuencia, también en el caso de los peces habría que tener en cuenta indicadores de bienestar animal.

SUMMARY: The emotional aspect of pain is not only controversial in fish and rodents, but also in self-conscious humans. When pain or dissatisfaction is seen as an intrinsic evil, avoiding it or at least minimizing it is a moral duty direct. The objective of this article is to refer to pain, stress and the most widely used indices of animal welfare both in laboratory fish (Danio rerio) and production fish (Salmo salar) as well as in rat experimental animal models (Rattus norvegicus) and mouse (Mus musculus).

Comparison of intraoperative nociception and postoperative acute pain after traditional or minimally invasive ovariohysterectomy in dogs

Many variations of ovariohysterectomy techniques have been described, including the traditional one and minimally invasive procedures. Non-laparoscopic Snook hook technique is an alternative for performing minimally invasive ovariohysterectomy. Few studies have been carried out in order to assess pain in animals submitted to minimally invasive surgeries, especially involving one of the most performed surgical procedures in veterinary practice. The aim of this study was to evaluate surgical duration, intraoperative nociception and acute postoperative pain after traditional ovariohysterectomy or minimally invasive non-laparoscopic technique in dogs using Snook hook. The hypothesis is that non-laparoscopic minimally invasive ovariohysterectomy would be faster and less painful than the conventional technique. Thirty dogs were divided into Traditional Group (TG = 15) and Minimally Invasive Group (MIG = 15). Heart rate, respiratory rate, systolic blood pressure, body temperature, oxyhemoglobin saturation, end-tidal carbon dioxide concentration (ETCO2) and end-tidal isoflurane concentration were evaluated before the surgery begins (M0), during incision (M1), clamping of the first ovarian pedicle (M2), second ovarian pedicle (M3), uterine cervix (M4), abdominal suture (M5) and at the end of surgery (M6). The modified Glasgow Pain Scale was used for acute postoperative pain assessment and Visual Analogue Scale (VAS) was used to assess the sensitivity of surgical wound. The level of significance established for all statistical analysis was 5%. Statistical differences were not observed between groups considering total surgical time and postoperative acute pain intensity (P > 0.05), in spite of MIG having shorter duration of surgery. There was no statistical difference between groups considering all intraoperative parameters except respiratory rate (TG < MIG; P < 0.05) and ETCO2 (MIG < TG; P < 0.05) at the moment of traction of the first ovarian pedicle (M2). Pain assessment by VAS showed statistical difference 24h after the end of surgery (TG < MIG) (P < 0.05). Both procedures were similar regarding intraoperative nociception and acute postoperative pain. It is possible that the sensation of pain in both procedures was blocked by the effectiveness of analgesics, once they might cause an inhibition of painful behaviors limiting a possible difference in pain identification. Higher respiratory stress observed in MIG at M2 and higher pain score by VAS noted in MIG 24 h after the end of surgery can be justified by greater traction of ovarian pedicle, due to limited surgical access of minimally invasive technique. Minimally invasive ovariohysterectomy non-laparoscopic seems to be potentially faster, probably due to the smaller size of the abdominal incision, which takes less time to be closed. In the present study, both techniques were performed by an experienced surgeon, providing safe procedures, nevertheless it is important to emphasize that iatrogenic injury can be caused by surgeons non-proficient in the Snook hook technique, considering the limited visualization of anatomical abdominal structures. Data obtained indicate that traditional ovariohysterectomy and non-laparoscopic Snook hook technique promote similar intraoperative nociception and acute postoperative pain, however minimally invasive procedure is potentially faster with less surgical trauma.(AU)

Effects of vitamin D administration on nociception and spinal cord pro-oxidant and antioxidant markers in a rat model of neuropathic pain

Reactive oxygen species (ROS) are involved in neuropathic pain, a complicated condition after nerve tissue lesion. Vitamin D appears to improve symptoms of pain and exhibits antioxidant properties. We investigated the effects of oral administration of vitamin D3, the active form of vitamin D, on nociception, the sciatic functional index (SFI), and spinal cord pro-oxidant and antioxidant markers in rats with chronic constriction injury (CCI) of the sciatic nerve, a model of neuropathic pain. Vitamin D3 (500 IU/kg per day) attenuated the CCI-induced decrease in mechanical withdrawal threshold and thermal withdrawal latency (indicators of antinociception) and SFI. The vitamin prevented increased lipid hydroperoxide levels in injured sciatic nerve without change to total antioxidant capacity (TAC). Vitamin D3 prevented increased lipid hydroperoxide, superoxide anion generation (SAG), and hydrogen peroxide (H2O2) levels in the spinal cord, which were found in rats without treatment at 7 and 28 days post-CCI. A significant negative correlation was found between mechanical threshold and SAG and between mechanical threshold and H2O2 at day 7. Vitamin D3 also prevented decreased spinal cord total thiols content. There was an increase in TAC in the spinal cord of vitamin-treated CCI rats, compared to CCI rats without treatment only at 28 days. No significant changes were found in body weight and blood parameters of hepatic and renal function. These findings demonstrated, for first time, that vitamin D modulated pro-oxidant and antioxidant markers in the spinal cord. Since antinociception occurred in parallel with oxidative changes in the spinal cord, the oxidative changes may have contributed to vitamin D-induced antinociception.

The Periaqueductal Gray and Its Extended Participation in Drug Addiction Phenomena / 神经科学通报·英文版

The periaqueductal gray (PAG) is a complex mesencephalic structure involved in the integration and execution of active and passive self-protective behaviors against imminent threats, such as immobility or flight from a predator. PAG activity is also associated with the integration of responses against physical discomfort (e.g., anxiety, fear, pain, and disgust) which occurs prior an imminent attack, but also during withdrawal from drugs such as morphine and cocaine. The PAG sends and receives projections to and from other well-documented nuclei linked to the phenomenon of drug addiction including: (i) the ventral tegmental area; (ii) extended amygdala; (iii) medial prefrontal cortex; (iv) pontine nucleus; (v) bed nucleus of the stria terminalis; and (vi) hypothalamus. Preclinical models have suggested that the PAG contributes to the modulation of anxiety, fear, and nociception (all of which may produce physical discomfort) linked with chronic exposure to drugs of abuse. Withdrawal produced by the major pharmacological classes of drugs of abuse is mediated through actions that include participation of the PAG. In support of this, there is evidence of functional, pharmacological, molecular. And/or genetic alterations in the PAG during the impulsive/compulsive intake or withdrawal from a drug. Due to its small size, it is difficult to assess the anatomical participation of the PAG when using classical neuroimaging techniques, so its physiopathology in drug addiction has been underestimated and poorly documented. In this theoretical review, we discuss the involvement of the PAG in drug addiction mainly via its role as an integrator of responses to the physical discomfort associated with drug withdrawal.

O modelo de dor inflamatória induzida pela carragenina como estratégia para avaliar a ação de drogas sobre a dor miofascial / The carrageenan-induced inflammatory pain model as a tool to assess the action of drugs on myofascial pain

A dor miofascial orofacial vem sendo tratada com analgésicos, anti-inflamatórios, relaxantes musculares, fisioterapia, laserterapia e placas oclusais. Contudo, muitas vezes, tais condutas falham em amenizar o quadro doloroso, havendo a necessidade de testar outras estratégias de tratamento. Metodologia: Uma opção para avaliação experimental dessas terapias seria o teste de dor induzido pela carragenina, associado ao teste de avaliação do limiar nociceptivo, originalmente desenvolvido para avaliar a ação de drogas nas patas de roedores. Sendo assim, o presente estudo analisou a nocicepção causada pela carragenina em masseteres de ratos, através do teste de Von Frey, correlacionando-a com alterações teciduais produzidas por esta droga. A carragenina foi injetada no músculo masseter de ratos, enquanto o grupo controle recebeu soro fisiológico. O limiar nociceptivo foi mensurado com um analgesímetro digital antes da administração da carragenina e 5 horas, 1, 3 e 7 dias após o seu uso. Decorridos 8 dias da intervenção, os animais foram eutanasiados, sendo seus masseteres encaminhados para processamento histológico e coloração H&E. Resultados: Observou-se uma diminuição do limiar da resposta nociceptiva em todos os períodos no grupo com carragenina, quando comparado com o grupo controle, havendo diferença estatisticamente significante nas 5 horas. A análise histológica do grupo experimental mostrou a presença de espaços perimisial e endomisial alargados e preenchidos por uma matriz com alguns linfócitos, muitos macrófagos e raros mastócitos. Conclusão: Os resultados indicaram que a associação de uma droga inflamatória com o método Von Frey pode ser uma opção para o estudo do efeito de terapias de dor miofascial.

Myofascial orofacial pain has been treated with analgesics, anti-inflammatories, muscle relaxants, physiotherapy, laser therapy and occlusal plaques. However, many times, such behaviors fail to alleviate the painful condition, with the need to test other treatment strategies. Methodology: An option for experimental evaluation of these therapies would be the pain test induced by carrageenan associated with the nociceptive threshold assessment test, originally developed to assess the action of drugs on the rodents' feet. Thus, the present study analyzed the nociception caused by carrageenan in rat masseter using the Von Frey test, correlating it with tissue changes produced by this drug. Carrageenan was injected into the masseter muscle of rats, while the control group received saline. The nociceptive threshold was measured with a digital analgesometer before administration of carrageenan and 5 hours, 1, 3 and 7 days after its use. After 8 days of the intervention, the animals were euthanized, and their masseters were sent for histological processing and H&E staining. Results: There was a decrease in the nociceptive response threshold in all periods in the group treated with carrageenan when compared to the control group, with a statistically significant difference at 5 hours. Histological analysis of the experimental group showed the presence of enlarged perimisial and endomisial spaces, filled by a matrix with some lymphocytes, many macrophages and rare mast cells. Conclusion: Results indicated that the association of an inflammatory drug with the Von Frey method may be an option for studying the effect of therapies on myofascial pain.

Guiding opioid-free intravenous antinociception with the Analgesia Nociception Index: a case report / Antinocicepção intravenosa sem opioides orientada pelo Índice de Analgesia/Nocicepção: relato de caso

Abstract Background: Opioid-free anesthesia decreases the incidence of opioid adverse events, but its optimal antinociceptive depth has not been clearly defined. Personalizing intraoperative opioid-free infusions with a nociception monitor may be the solution. Case report: We describe the feasibility and potential limitations of titrating opioid-free antinociception during major abdominal surgery using the Analgesia Nociception Index (Mdoloris, Lille, France) in an obese patient. After stabilizing the patient's nociception-antinociception balance intraoperatively we quickly reversed anesthesia and the patient did not require postoperative opioids. Conclusion: Personalizing opioid-free antinociception with a nociception monitor is feasible. It may optimize intraoperative antinociception and improve postoperative comfort.

Resumo Introdução A anestesia sem opioides diminui a incidência de eventos adversos associados aos opioides, mas a profundidade antinociceptiva ideal dessa abordagem não está claramente definida. Personalizar a infusão intraoperatória sem opioides com o uso de monitor de nocicepção pode ser a solução. Relato de caso Descrevemos a viabilidade e as eventuais limitações da titulação da antinocicepção sem opioides por meio do uso do Índice de Analgesia/Nocicepção (Mdoloris, Lille, França) durante cirurgia abdominal de grande porte em paciente com obesidade. Depois de estabilizar o equilíbrio nocicepção-antinocicepção da paciente no intraoperatório, revertemos rapidamente a anestesia e a paciente não precisou de opioides no pós-operatório. Conclusão A personalização da antinocicepção sem opioides por meio do emprego de monitor de nocicepção é factível. A abordagem pode otimizar a antinocicepção intraoperatória e melhorar o conforto pós-operatório.

Dolor en Aves y Peces / Pain in Birds and Fish

Se ha demostrado que aves y peces presentan estructuras anatómicas similares a las que transducen el dolor en humanos y, además, muestran respuestas negativas frente a estímulos nocivos, junto a cambios conductuales. De acuerdo con esto, existe una responsabilidad moral frente al uso de estos animales en investigación para evitar y/o minimizar el dolor.

Birds and fish have been shown to present anatomical structures similar to those that transduce pain in humans, and also show negative responses to harmful stimuli, along with behavioural changes. There is a moral responsibility regarding the use of these animals in research to avoid and/or minimize pain. In this review we compare the pain-related morphology of birds and fish, using pain in humans as a starting point.

Neuronas participantes en la modalidad sensorial del dolor bucofacial de la periferia hasta el encéfalo / Neurons involved in the sensory modality of orofacial pain from periphery to encephalon

Introducción: El dolor proveniente de cabeza y cuello se vincula a la vía trigeminal, y participan tres neuronas: neurona de primer orden ubicada en ganglio trigeminal; neurona de segundo orden, en el subnúcleo caudal del nervio trigémino; y la neurona de tercer orden que parte de la zona medial del complejo ventrobasal de tálamo y termina en la corteza cerebral. Objetivo: Interpretar que el daño tisular, mediante impulsos nerviosos es transmitido por una cadena de neuronas hasta el encéfalo. Contenido: Las neuronas de primer orden, sus cuerpos neuronales se encuentran ubicados en el ganglio espinal del trigémino, en hueso temporal. En el subnúcleo caudal, se ubican las neuronas de segundo orden que reciben estímulos nociceptivos y de temperatura de la cara y la boca; sus axones se cruzan en la extensión de este subnúcleo, y ascienden contralateralmente, y establecen sinapsis en el tálamo con neuronas de tercer orden. En el encéfalo no hay un único "centro del dolor", las neuronas de tercer orden, terminan en diferentes áreas de la corteza cerebral que se reconocen como "matriz del dolor". Consideraciones finales: Tres conjuntos de neuronas conforman la vía nociceptiva trigeminal, la primera ubicada en el ganglio trigeminal fuera del sistema nervioso central y los otros dos conjuntos neuronales conforman núcleos dentro del mismo(AU)

Introduction: Pain from the head and neck is linked to the trigeminal pathway and three neurons participate: a first-order neuron located in the trigeminal ganglion, a second-order neuron from the subnucleus caudalis of the trigeminal nerve, and a third-order neuron which starts from the medial area of the ventrobasal thalamus complex and ends in the cerebral cortex. Objective: Describe the way in which a chain of neurons transmit tissue damage to the encephalon by means of nerve impulses. Content: In first-order neurons, their neuronal bodies are located in the trigeminal spinal ganglion, in temporal bone. In the subnucleus caudalis, second-order neurons are found which receive nociceptive and temperature stimuli from the face and mouth. Their axons cross over the extension of this subnucleus, ascend contralaterally and establish synapses with third-order neurons in the thalamus. In the encephalon there is not a single "pain center": third-order neurons end in different areas of the cerebral cortex recognized as the "pain matrix". Final considerations: Three sets of neurons make up the trigeminal nociceptive pathway. The first one is located in the trigeminal ganglion outside the central nervous system whereas the other two form nuclei within it(AU)

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.

Unveiling the Insular Lobe of Reil: Neurophysiological and Anatomical Features

The insular lobe has long been investigated, from its anatomical descriptions to its neurophysiological activity. Located in a central location, the insular lobe participates in several afferent and efferent pathways, forming part of the eloquent and fundamental structures that make up the central core of the brain. The lobe of the insula has participation in language function, such as speech, sensory (e.g., taste), limbic, autonomic (visceral), also forming part of complex associative circuits, including part of the circuits of mirror neurons. Several functional descriptions attributed to the insular lobe have beenmade in patients suffering fromcerebrovascular diseases, as well as in those with epilepsy. Much progress and many descriptions have also been made in patients with tumors. Despite much information already available about the insular lobe, it is likely that much will be discovered in the coming years.

Effects of Intraperitoneal N-methyl-D-aspartate (NMDA) Administration on Nociceptive/Repetitive Behaviors in Juvenile Mice

Dysregulation of excitatory neurotransmission has been implicated in the pathogenesis of neuropsychiatric disorders. Pharmacological inhibition of N-methyl-D-aspartate (NMDA) receptors is widely used to model neurobehavioral pathologies and underlying mechanisms. There is ample evidence that overstimulation of NMDA-dependent neurotransmission may induce neurobehavioral abnormalities, such as repetitive behaviors and hypersensitization to nociception and cognitive disruption, pharmacological modeling using NMDA has been limited due to the induction of neurotoxicity and blood brain barrier breakdown, especially in young animals. In this study, we examined the effects of intraperitoneal NMDA-administration on nociceptive and repetitive behaviors in ICR mice. Intraperitoneal injection of NMDA induced repetitive grooming and tail biting/licking behaviors in a dose- and age-dependent manner. Nociceptive and repetitive behaviors were more prominent in juvenile mice than adult mice. We did not observe extensive blood brain barrier breakdown or neuronal cell death after peritoneal injection of NMDA, indicating limited neurotoxic effects despite a significant increase in NMDA concentration in the cerebrospinal fluid. These findings suggest that the observed behavioral changes were not mediated by general NMDA toxicity. In the hot plate test, we found that the latency of paw licking and jumping decreased in the NMDA-exposed mice especially in the 75 mg/kg group, suggesting increased nociceptive sensitivity in NMDA-treated animals. Repetitive behaviors and increased pain sensitivity are often comorbid in psychiatric disorders (e.g., autism spectrum disorder). Therefore, the behavioral characteristics of intraperitoneal NMDA-administered mice described herein may be valuable for studying the mechanisms underlying relevant disorders and screening candidate therapeutic molecules.

Morphological and nociceptive effects of mechanical vibration on the sciatic nerve of oophorectomized Wistar rats

Aim: To evaluate the effects of whole-body vibration in the sciatic nerve of oophorectomized Wistar rats, on nociceptive and morphological parameters, such as fiber, axon, and myelin sheath diameters, G ratio, number of nerve fiber and nuclei of Schwann cells, and percentage of connective tissue. Method: Sixty-four rats were used in the groups sham-operate and oophorectomy (n = 32/group); after surgical procedures, each group was subdivided into four: euthanized in the 12th week, untreated and treated for four weeks; and euthanized in the 16th week, untreated and treated for eight weeks. The treatment with vibration was performed with a 60 Hz frequencies, for 10 minutes, three days a week, with duration of 4 or 8 weeks. Nociception was evaluated later, in the right paw, by means of a digital analgesimeter, prior to surgery, at the beginning and at the end of the protocol. After the trial period, the sciatic nerve was dissected for examination of the general morphology of the tissue and morphometric analysis; later, the animals were euthanized. Results: Regarding nociception and the morphometry of the sciatic nerve, independent of oophorectomy and treatment time, there was no statistically significant difference within and between groups. Also, the general morphology of the tissue in all groups had characteristics that were preserved. Conclusion: The mechanical vibration did not alter the nociceptive threshold and the morphological aspects of nerve fibers in oophorectomized Wistar rats.(AU)

An overview of analgesics: NSAIDs, paracetamol, and topical analgesics

Pain is a complex and unique experience. It encompasses several pathways, involving nociceptive signal generation (transduction) and propagation (transmission), as well as perception and modulation of the nociceptive stimuli. Nonsteroidal anti-inflammatory drugs (NSAIDs) primarily exert their analgesic effects through inhibition of cyclooxygenase (COX) enzymes, thereby attenuating prostaglandin synthesis. The COX-2 selective NSAIDs (coxibs) and aspirin have also been shown to reduce colorectal cancers,presumably by prostaglandin-inhibition mechanisms. Paracetamol appears to have both peripheral and central effects. The postulated mechanism for its peripheral effects is indirect COX inhibition, while the central effects are thought to be mediated by modulation of descending pain inhibition pathways. Topical analgesics are available in various formulations. The topical NSAIDs have the same mechanism of action as the systemic formulations, but with less systemic absorption and effects. The local anaesthetics provide a dense sensory block via inhibition of nerve impulse transmission, and are available in percutaneous and transdermal preparations. Capsicum is effective forneuropathic pain, and acts by stimulating and then desensitising peripheral sensory nerves

Vagal Transient Receptor Potential Ankyrin 1 Mediates Stress-exacerbated Visceral Mechanonociception After Antral Cold Exposure

BACKGROUND/AIMS: Abdominal pain can be evoked or exacerbated after gastrointestinal cold stimulation in some patients with diarrhea-predominant irritable bowel syndrome (IBS-D), indicating a low temperature-induced sensitization of visceral perception. We investigated the role of vagal transient receptor potential ankyrin 1 (TRPA1, a cold-sensing ion channel) in cold-aggravated visceral mechanonociception in a stress-induced IBS animal model. METHODS: TRPA1 expression was examined in antral biopsies of healthy controls and IBS-D patients. Abdominal symptoms were assessed before and after warm or cold water intake. The visceromotor response (VMR) to colorectal distention (CRD) following intra-antral infusion of cold saline was measured in animals undergoing sham or chronic water avoidance stress. TRPA1 expression, extracellular signal-regulated protein kinase 1/2 (ERK1/2) phosphorylation, and neuronal calcium influx in vagal afferents were assessed. RESULTS: Compared to healthy controls, IBS-D patients displayed elevated antral TRPA1 expression, which was associated with symptom scores after cold (4°C) water intake. Intra-antral infusion of cold saline increased VMR to CRD in naive rats, an effect dependent on vagal afferents. In stressed rats, this effect was greatly enhanced. Functional blockade and gene deletion of TRPA1 abolished the cold effect on visceral nociception. TRPA1 expression in vagal (but not spinal) afferents increased after stress. Moreover, the cold-induced, TRPA1-dependent ERK1/2 activation and calcium influx in nodose neurons were more robust in stressed rats. CONCLUSIONS: Stress-exaggerated visceral mechanonociception after antral cold exposure may involve up-regulation of TRPA1 expression and function on vagal afferents. Our findings reveal a novel mechanism for abnormal gastrointestinal cold sensing in IBS.

Nociception monitoring tools using autonomic tone changes for intraoperative analgesic guidance in pediatric patients

Nociception monitoring devices using changes in autonomic nervous system activity have been developed in numerous ways. Although there have been few studies conducted on children, compared to the relatively higher number of studies on adults, most of the nociception monitors in children, as in adults, appear to be more useful than the standard clinical practice that uses hemodynamic parameters in the evaluation and treatment of intraoperative nociception (pain) during general anesthesia. Particularly, when monitoring the surgical pleth index (SPI) in anesthetized children, the application of a new target range of SPI values (≤ 40) to the SPI monitoring criteria seems to be necessary for providing a more proper intraoperative analgesia. The analgesia nociception index (ANI) shows promising results in anesthetized adults, and recently, positive results along with cardiorespiratory coherence have been reported in pediatric patients. Newborn infant parasympathetic evaluation (NIPE) could be useful for providing adequate analgesia in newborns, infants, and children under 2 years of age in anesthetized or awake states. In cases of skin conductance and pupillometry, further studies are needed. Understanding the pros, cons, and limitations of these nociception monitoring tools will provide more effective and safe intraoperative analgesia to pediatric patients undergoing general anesthesia, and it may also help to plan and conduct promising research on the use of perioperative nociception monitoring in pediatric patients in the future.

Combination of a Rapidly Penetrating Agonist and a Slowly Penetrating Antagonist Affords Agonist Action of Limited Duration at the Cellular Level

The capsaicin receptor TRPV1 (transient receptor potential vanilloid 1) has been an object of intense interest for pharmacological development on account of its critical role in nociception. In the course of structure activity analysis, it has become apparent that TRPV1 ligands may vary dramatically in the rates at which they interact with TRPV1, presumably reflecting differences in their abilities to penetrate into the cell. Using a fast penetrating agonist together with an excess of a slower penetrating antagonist, we find that we can induce an agonist response of limited duration and, moreover, the duration of the agonist response remains largely independent of the absolute dose of agonist, as long as the ratio of antagonist to agonist is held constant. This general approach for limiting agonist duration under conditions in which absolute agonist dose is variable should have more general applicability.

Anti-nociceptive and Anti-inflammatory Properties of Ilex latifolia and its Active Component, 3,5-Di-caffeoyl Quinic Acid Methyl Ester

The present study was conducted to investigate anti-nociceptive and anti-inflammatory effects of the leaves of Ilex latifolia Thunb (I. latifolia) in in vivo and in vitro. Writhing responses induced by acetic acid and formalin- and thermal stimuli (tail flick and hot plate tests)-induced pain responses for nociception were evaluated in mice. I. latifolia (50 – 200 mg/kg, p.o.) and ibuprofen (100 mg/kg, p.o.), a positive non-steroidal anti-inflammatory drug (NSAID), inhibited the acetic acid-induced writhing response and the second phase response (peripheral inflammatory response) in the formalin test, but did not protect against thermal nociception and the first phase response (central response) in the formalin test. These results show that I. latifolia has a significant anti-nociceptive effect that appears to be peripheral, but not central. Additionally, I. latifolia (50 and 100 µg/mL) and 3,5-di-caffeoyl quinic acid methyl ester (5 µM) isolated from I. latifolia as an active compound significantly inhibited LPS-induced NO production and mRNA expression of the pro-inflammatory mediators, iNOS and COX-2, and the pro-inflammatory cytokines, IL-6 and IL-1β, in RAW 264.7 macrophages. These results suggest that I. latifolia can produce antinociceptive effects peripherally, but not centrally, via anti-inflammatory activity and supports a possible use of I. latifolia to treat pain and inflammation.

Potentiation of the glycine response by serotonin on the substantia gelatinosa neurons of the trigeminal subnucleus caudalis in mice

The lamina II, also called the substantia gelatinosa (SG), of the trigeminal subnucleus caudalis (Vc), is thought to play an essential role in the control of orofacial nociception. Glycine and serotonin (5-hydroxytryptamine, 5-HT) are the important neurotransmitters that have the individual parts on the modulation of nociceptive transmission. However, the electrophysiological effects of 5-HT on the glycine receptors on SG neurons of the Vc have not been well studied yet. For this reason, we applied the whole-cell patch clamp technique to explore the interaction of intracellular signal transduction between 5-HT and the glycine receptors on SG neurons of the Vc in mice. In nine of 13 neurons tested (69.2%), pretreatment with 5-HT potentiated glycine-induced current (I(Gly)). Firstly, we examined with a 5-HT₁ receptor agonist (8-OH-DPAT, 5-HT(1/7) agonist, co-applied with SB-269970, 5-HT₇ antagonist) and antagonist (WAY-100635), but 5-HT₁ receptor agonist did not increase IGly and in the presence of 5-HT₁ antagonist, the potentiation of 5-HT on I(Gly) still happened. However, an agonist (α-methyl-5-HT) and antagonist (ketanserin) of the 5-HT₂ receptor mimicked and inhibited the enhancing effect of 5-HT on I(Gly) in the SG neurons, respectively. We also verified the role of the 5-HT₇ receptor by using a 5-HT₇ antagonist (SB-269970) but it also did not block the enhancement of 5-HT on I(Gly). Our study demonstrated that 5-HT facilitated I(Gly) in the SG neurons of the Vc through the 5-HT₂ receptor. The interaction between 5-HT and glycine appears to have a significant role in modulating the transmission of the nociceptive pathway.

Diverse characters of Brennan’s paw incision model regarding certain parameters in the rat / 대한통증학회지

BACKGROUND: Brennan’s rodent paw incision model has been extensively used for understanding mechanisms underlying postoperative pain in humans. However, alterations of physiological parameters like blood pressure and heart rate, or even feeding and drinking patterns after the incision have not been documented as yet. Moreover, though eicosanoids like prostaglandins and leukotrienes contribute to inflammation, tissue levels of these inflammatory mediators have never been studied. This work further investigates the antinociceptive effect of protein C after intra-wound administration. METHODS: Separate groups of Sprague–Dawley rats were used for quantitation of cyclooxygenase (COX) activity and leukotriene B4 level by enzyme-linked immunosorbent assay, as well as estimation of cardiovascular parameters and feeding and drinking behavior after paw incision. In the next part, rats were subjected to incision and 10 μg of protein C was locally administered by a micropipette. Both evoked and non-evoked pain parameters were then estimated. RESULTS: COX, particularly COX-2 activity and leukotriene B4 levels increased after incision. Hemodynamic parameters were normal. Feeding and drinking were affected on days 1 and 3, and on day 1, respectively. Protein C attenuated non-evoked pain behavior alone up to day 2. CONCLUSIONS: Based upon current observations, Brennan’s rodent paw incision model appears to exhibit a prolonged period of nociception similar to that after surgery, with minimal interference of physiological parameters. Protein C, which is likely converted to activated protein C in the wound, attenuated the guarding score, which probably represents pain at rest after surgery in humans.