Molecular aspects involved in the mechanisms of Bothrops jararaca venom-induced Hyperalgesia: participation of NK1 Receptor and glial cells

Accidents caused by Bothrops jararaca (Bj) snakes result in several local and systemic manifestations, with pain being a fundamental characteristic. The inflammatory process responsible for hyperalgesia induced by Bj venom (Bjv) has been studied; however, the specific roles played by the peripheral and central nervous systems in this phenomenon remain unclear. To clarify this, we induced hyperalgesia in rats using Bjv and collected tissues from dorsal root ganglia (DRGs) and spinal cord (SC) at 2 and 4 h post-induction. Samples were labeled for Iba-1 (macrophage and microglia), GFAP (satellite cells and astrocytes), EGR1 (neurons), and NK1 receptors. Additionally, we investigated the impact of minocycline, an inhibitor of microglia, and GR82334 antagonist on Bjv-induced hyperalgesia. Our findings reveal an increase in Iba1 in DRG at 2 h and EGR1 at 4 h. In the SC, markers for microglia, astrocytes, neurons, and NK1 receptors exhibited increased expression after 2 h, with EGR1 continuing to rise at 4 h. Minocycline and GR82334 inhibited venom-induced hyperalgesia, highlighting the crucial roles of microglia and NK1 receptors in this phenomenon. Our results suggest that the hyperalgesic effects of Bjv involve the participation of microglial and astrocytic cells, in addition to the activation of NK1 receptors.

Hipernocicepção induzida por veneno de serpentes Bothrops jararaca: uma revisão de literatura

Since the beginning of humanity, man has experienced the subjectivity and complexity of pain, an essential phenomenon for the preservation of physical integrity. Pain processing occurs by transmission, transduction, modulation and perception of stimuli capable of activating nociceptors. There are many substances that activate nociceptors, among them are animal venoms, such by snakes, which have a highly complex composition. In Brazil, the most important snakes belong to the genus Bothrops. Conventional treatment with antivenom is effective against systemic symptoms, but not very effective in controlling local lesions, such as edema and pain. The main actions of Bothrops venoms are in hemostasis and inflammation, the latter condition being responsible for causing the sensitization of nociceptors. Some venom substances are involved in inflammation and hypernociception, including jararhagin, a metalloprotease present in Bothrops jararaca venom (BjV). Through a literature review, we seek to understand the mechanisms that leads to hypernociception caused by BjV. The scientific literature regarding the mediation of pain induced by BjV is scarce, even more so in relation to sex differences, a variable little considered in the genesis and treatment of the lesions observed after envenomation by these snakes. Thus, further studies are needed to elucidate the mechanisms involved in hypernociception resulting from the Bothrops jararaca snakebites, with the aim of mapping this phenomenon and, in the future, seeking complementary therapies to the conventional one in the treatment of these symptoms.

Desde o surgimento da humanidade o homem vivencia a subjetividade e complexidade da dor, fenômeno essencial para a preservação da integridade física. O processamento da dor ocorre pela transmissão, transdução, modulação e percepção de estímulos capazes de ativar os nociceptores. Muitas são as substâncias que ativam os nociceptores, dentre elas estão os venenos animais, como por exemplo de serpentes, que possuem uma composição altamente complexa. No Brasil, as serpentes de maior importância pertencem ao gênero Bothrops. O tratamento convencional com antiveneno é efetivo contra as reações sistêmicas, porém pouco eficaz no controle das lesões locais, como edema e dor. As principais ações dos venenos botrópicos são na hemostasia e inflamação, sendo essa última condição responsável por causar a sensibilização dos nociceptores. Algumas toxinas dos venenos estão envolvidas na inflamação e hipernocicepção, dentre elas a jararagina, uma metaloprotease presente no veneno de Bothrops jararaca (vBj). Por meio de uma revisão de literatura buscamos compreender os mecanismos que levam a hipernocicepção causada pelo vBj. A literatura científica a respeito da mediação da dor promovida pelo vBj é escassa, mais ainda, em relação às diferenças sexuais, uma variável pouco considerada na gênese e no tratamento das lesões observadas após o envenenamento por essas serpentes. Desta forma, mais estudos são necessários para elucidar os mecanismos envolvidos na hipernocicepção decorrente da picada de serpentes Bothrops jararaca, com o intuito de mapear esse fenômeno e futuramente buscar terapias complementares à convencional no tratamento desse sintoma.

Mechanical hyperalgesia in athletes' shoulder: integrative review / Hiperalgesia mecânica no ombro de atletas: revisão integrativa

ABSTRACT BACKGROUND AND OBJECTIVES: Chronic shoulder pain in throwing athletes is a common complaint in everyday practice. Despite the growing number of publications, it is unclear whether these athletes have mechanical hyperalgesia associated with pain, which could alter the treatment options undertaken. The aim of the study was to summarize the results of the main evidence found on the pressure pain threshold in the shoulder, to compare these results in athletes of different sports. METHODS: Electronic search via PubMed/Medline, PEDro, SPORTDiscuss, Web of Science and Scielo databases was done verifying studies in English or Portuguese. The keywords: pressure pain threshold; athletes; shoulder; pressure algometry and its derivations were searched in both languages. The articles should have included athletes from sports that use upper limbs and that assess the pressure pain threshold in the shoulder. Five studies were included for analysis. RESULTS: Athletes with shoulder pain had a lower pressure pain threshold. In swimmers, changes in mechanical sensitivity to pain seem to be related to weekly training hours, years of sports practice and age group. Sports competitions apparently have an influence on the reduction of pressure pain threshold in amateur tennis players. CONCLUSION: Swimming athletes have a lower pressure pain threshold and this is related to the volume and time of training in the modality. This variable seems to be sport-dependent, and the absence of a greater number of studies in sports such as tennis and wheelchair basketball limits conclusions on this subject.

RESUMO JUSTIFICATIVA E OBJETIVOS: A dor crônica no ombro de atletas arremessadores é uma queixa comum no cotidiano do esporte. Apesar do número crescente de publicações sobre o tema, não está claro se esses atletas apresentam hiperalgesia mecânica associada a dor, o que poderia alterar as abordagens de tratamento realizadas. O objetivo da presente pesquisa foi sintetizar os resultados das principais evidências encontradas sobre o limiar de dor a pressão no ombro, comparando estes resultados em esportistas de diversas modalidades. MÉTODOS: Para esta revisão integrativa, as buscas eletrônicas ocorreram nas bases de dados Pubmed/Medline, PEDro, SPORTDiscuss, Web of Science e Scielo, verificando estudos em inglês ou português. As palavras-chave pressure pain threshold; athletes; shoulder; pressure algometry e suas derivações foram pesquisadas em ambas as linguagens. Os artigos deveriam incluir atletas de esportes com gestos esportivos no membro superior e que avaliassem o limiar de dor a pressão no ombro. Cinco estudos foram incluídos para análise. RESULTADOS: Atletas com dor no ombro apresentaram menor limiar de dor a pressão. Em nadadores, as alterações na sensibilidade mecânica a dor parecem estar relacionadas com horas de treino semanais, anos de prática esportiva e faixa etária. As competições esportivas aparentemente possuem influência na redução do limiar de dor a pressão em tenistas amadores. CONCLUSÃO: Atletas de natação apresentam menor limiar de dor a pressão, o qual se relaciona com o volume e tempo de treinamento na modalidade. Essa variável parece ser esporte-dependente, e a ausência de um maior número de estudos em esportes como tênis e basquete em cadeiras de rodas limita conclusões acerca do assunto. DESTAQUES Dor no ombro é uma condição comum em atletas overhead e atletas com dor no ombro apresentam alterações no limiar de dor a pressão (LDP). Na natação, o LDP parece sofrer influência do volume de treinamento semanal, de anos de prática da modalidade e da faixa etária. Alterações no LDP em tenistas e jogadores de basquete em cadeira de rodas ainda carecem de dados mais conclusivos.

Effect of photobiomodulation therapy (660 nm and 830 nm) on carrageenan-induced edema and pain behavior in mice / Efeito da terapia por fotobiomodulação (660 nm e 830 nm) no comportamento da dor e edema induzidos por carragenina em camundongos

ABSTRACT BACKGROUND AND OBJECTIVES: Photobiomodulation (PBM) is an important therapeutic tool for inflammatory process modulation. In this study, the anti-inflammatory and analgesic effect of two different energies and two different wavelengths (660 nm and 830 nm) were investigate and compared through the model of carrageenan-induced paw edema in mice. METHODS: Male Swiss mice, 36 animals (n=6 animals/group) were divided into six groups: Group 1 (saline-control), Group 2 (carrageenan), Group 3 (carrageenan + laser 660 nm, 5.88 J), Group 4 (carrageenan + laser 660 nm, 2.94 J), Group 5 (carrageenan + laser 830 nm, 5.88 J), and Group 6 (carrageenan + laser 830 nm, 2.94 J). PBM was applied 1h after the carrageenan injection which induced paw edema and hyperalgesia, which were measured by means of a plethysmometer and by flicker test using a water bath at 38ºC (±0.5ºC), respectively. Left paws of mice injected with carrageenan exhibited local edema that persisted for up to 6h after its administration. All animals were evaluated before, 1, 2, 3, 4, and 6 h after the injection of carrageenan. RESULTS: PBM, specially the 830 nm wavelength with 2.94 J of energy, reduced the paw edema induced by carrageenan. In addition, the 660 nm wavelengths (5.88 J / 2.94 J) and 830 nm (2.94 J) inhibited thermal hyperalgesia induced by carrageenan after 4 h of paw injection. CONCLUSION: There was evidence that the PBM 830 nm (2.94 J) produced a more pronounced anti-inflammatory effect, while the 660 nm (5.88 J / 2.94 J) energy laser was more effective to inhibit the hyperalgesia response induced by the carrageenan injection.

RESUMO JUSTIFICATIVA E OBJETIVOS: A fotobiomodulação (FBM) é uma importante ferramenta terapêutica para modulação dos processos inflamatórios. Neste estudo, investigou-se o efeito anti-inflamatório e analgésico de duas energias e dois comprimentos de onda diferentes (660 nm e 830 nm) através do modelo de edema de pata induzido por carragenina em camundongos. MÉTODOS: Trinta e seis camundongos Swiss machos (n=6 animais/grupo) foram divididos em seis grupos: Grupo 1 (controle salino), Grupo 2 (carragenina), Grupo 3 (carragenina + laser 660 nm, 5,88 J), Grupo 4 (carragenina + laser 660 nm, 2,94 J), Grupo 5 (carragenina + laser 830 nm, 5,88 J) e Grupo 6 (carragenina + laser 830 nm, 2,94 J). A FBM foi aplicada 1h após a injeção de carragenina que induziu o edema de pata e a hiperalgesia térmica, os quais foram medidos por meio de um pletismômetro e pelo flicker test em banho-maria a 38ºC (±0,5ºC), respectivamente. As patas esquerdas injetadas com carragenina apresentaram edema local que persistiu por até 6h após sua administração. Todos os animais foram avaliados antes, 1, 2, 3, 4, e 6 horas após a injeção de carragenina. RESULTADOS: A FBM, principalmente o comprimento de onda 830 nm com 2,94 J de energia, reduziu o edema de pata induzido pela carragenina. Além disso, o comprimento de onda 660 nm (5,88 J / 2,94 J) e o 830 nm (2,94 J) inibiram a hiperalgesia térmica induzida pela carragenina após 4h da injeção na pata. CONCLUSÃO: Evidenciou-se que a FBM 830 nm (2,94 J) produziu efeito anti-inflamatório mais pronunciado, enquanto o laser de 660 nm (5,88 J / 2,94 J) de energia foi mais eficaz para reduzir a resposta de hiperalgesia induzida pela injeção de carragenina.

Pain and cellular migration induced by Bothrops jararaca venom in mice selected for an acute inflammatory response: involvement of mast cells

Bothrops jararaca venom (BjV) can induce mast cell degranulation. In order to investigate the role of mast cells and the interference of the host genetic background in the inflammation induced by BjV, we have used mouse strains selected for maximal (AIRmax) or minimal (AIRmin) acute inflammatory response (AIR). Mice were pretreated with an inhibitor of mast cell degranulation, cromolyn (CROM), and injected in footpads or intraperitoneally (i.p.) with BjV. Pain was measured with von Frey hairs, cell migration in the peritoneum by flow cytometry, and reactive oxygen species (ROS) production by chemiluminescence assays. The nociceptive response to BjV was higher in AIRmax than AIRmin mice; however, this difference was abolished by pretreatment with CROM. BjV induced peritoneal neutrophil (CD11b+ GR-1+) infiltration and ROS secretion in AIRmax mice only, which were partially inhibited by CROM. Our findings evidence a role for mast cells in pain, neutrophil migration, and ROS production triggered by BjV in AIRmax mice that are more susceptible to the action of BjV.

Neuroprotective role of Tinospora cordifolia extract in streptozotocin induced neuropathic pain

Abstract Diabetic Neuropathy (DN) is one of the prevailing micro vascular complications of diabetes which can be characterized by neuropathic pain. Streptozotocin (STZ) induced diabetes in the rat has been increasingly used as a model of painful diabetic neuropathy. STZ injection leads to neurotoxicity of peripheral nerves that leads to development of Peripheral Diabetic Neuropathy in rat model. The present study was aimed at exploring the protective role of Tinospora cordifolia extract in STZ induced neurotoxicity and evaluating mechanisms responsible for attenuating neuropathic pain. Neuropathic pain markers like hyperalgesia, allodynia and motor deficits were assessed before STZ injection and after the treatment with 250 mg/kg and 500 mg/kg dose of Tinospora cordifolia. Oxidative stress markers, NGF expression in sciatic nerve were observed after seven weeks treatment. Our results demonstrated that seven weeks treatment with Tinospora cordifolia leaf extract significantly relieved thermal hyperalgesia and allodynia by increasing the antioxidant enzyme levels, decreasing the lipid peroxidation and by increasing the Nerve growth factor (NGF) expression in diabetic rat sciatic nerves. Our findings highlighted the beneficial effects of oral administration of Tinospora cordifolia extract in attenuating diabetic neuropathic pain, possibly through a strong antioxidant activity and by inducing NGF m RNA in sciatic nerves.

Comparative study of cold hyperalgesia and mechanical allodynia in two animal models of neuropathic pain: different etiologies and distinct pathophysiological mechanisms

Abstract Neuropathic pain (NP) affects more than 8% of the global population. The proposed action of the transient receptor potential ankyrin 1 (TRPA1) as a mechanosensor and the characterization of the transient receptor potential melastatin 8 (TRPM8) as a cold thermosensor raises the question of whether these receptors are implicated in NP. Our study aimed to evaluate the involvement of TRPA1 and TRPM8 in cold and mechanical signal transduction to obtain a comparative view in rat models of streptozotocin-induced diabetes (STZ) and chronic constriction injury of the sciatic nerve (CCI). The electronic von Frey test showed that STZ rats presented mechanical allodynia that was first evidenced on the 14th day after diabetes confirmation, and four days after CCI. This phenomenon was reduced by the intraplantar (ipl) administration of a TRPA1 receptor antagonist (HC-030031; 40 µL/300 µg/paw) in both NP models. Only CCI rats displayed cold hyperalgesia based on the cold plate test. The pharmacological blocking of TRPA1 through the injection of the antagonist attenuated cold hyperalgesia in this NP model. STZ animals showed a reduction in the number of flinches induced by the intraplantar injection of mustard oil (MO; TRPA1 agonist; 0.1%/50 µL/paw), or intraplantar injection of menthol (MT; TRPM8 agonist; 0.5% and 1%/50 µL/paw). The response induced by the ipl administration of MT (1%/50 µL/paw) was significantly different between the CCI and SHAM groups. Together, these data suggest a different pattern in nociceptive behavior associated with different models of NP, suggesting a variant involvement of TRPA1 and TRPM8 in both conditions

Alleviation of neuropathic pain by trazodone in rats

Abstract Neuropathic pain is generally characterised by an abnormal sensation (dysesthesia), an increased response to painful stimuli (hyperalgesia), and pain in response to a stimulus that does not normally provoke pain (allodynia). The present study was designed to investigate the effect of trazodone (5mg/kg and 10mg/kg) on peripheral neuropathic pain induced by partial sciatic nerve ligation in rats. Mechanical hyperalgesia, cold allodynia and thermal hyperalgesia were assessed by performing the pinprick, acetone, and hot plate tests, respectively. Biochemically, lipid peroxidation level and total calcium levels were measured. However, trazodone administration (5 and 10 mg/ kg i.p.) for 21days significantly diminished partial sciatic nerve ligation-induced neuropathic pain along with areduction in oxidative stress and calcium levels. The results of the present study suggest that trazodone is effective in attenuating partial sciatic nerve ligation-inducedpainful neuropathic states, which may be attributed to decreased oxidative stress and calcium levels.

Dolor de rebote en anestesia regional: Una revisión narrativa / Rebound pain in regional anesthesia: A narrative review Abstract

OBJECTIVES: To describe the phenomenon of rebound pain associated with peripheral nerve blocks in the setting of trauma and orthopedic surgery, to know its characteristics, pathophysiological mechanisms, risk factors, preventive and treatment measures. METHODOLOGY: Non-systematic bibliographic review of articles in English, in medical databases PubMed, Google Scholar, Embase, Epistemonikos and Cochrane library in January 2021, restricting the search to articles published in the last five years. A total of 58 articles related to rebound pain in the context of orthopedic and trauma surgery were identified according to the inclusion and exclusion criteria. RESULTS: It was evidenced that there is still no consensus on its definition, although it presents repeated characteristics, such as acute and transitory pain, which occurs after the resolution of the peripheral nerve block. An incidence of up to 50% is described in the outpatient setting, but there is no data outside this setting. Its pathophysiology is complex and not yet fully understood, however, a peripheral sensitization component could determine a higher incidence of the phenomenon. Recognized risk factors correspond to trauma and orthopedic surgeries of the upper limb with dense peripheral nerve blocks and young female patients. In relation to its prevention, dexamethasone and dexmedetomidine stand out as promising adjuvants that together with a multimodal analgesia scheme can mitigate its appearance. CONCLUSIONS: Understanding the impact of rebound pain, its characteristics, risk factors, preventive measures and benefits of multimodal analgesia, is part of a comprehensive clinical practice to avoid the negative consequences of increased use of health resources, as well as to reduce the consumption of opioids and their known adverse effects.

OBJETIVOS : Describir el fenómeno de dolor de rebote asociado a bloqueos de nervio periférico en el entorno de cirugía traumatoló- gica y ortopédica, conocer sus características, mecanismos fisiopatológicos, factores de riesgo, medidas preventivas y de tratamiento. METODOLOGÍA: Revisión bibliográfica no sistemática de artículos en inglés, en bases de datos médicas PubMed, GoogleScholar, Embase, Epistemonikos y Cochrane library en enero del 2021, restringiéndose la búsqueda a los artículos publicados en los últimos cinco años. Se identificaron un total de 67 artículos relacionados a dolor de rebote en contexto de cirugía ortopédica y traumatológica según los criterios de inclusión y exclusión. RESULTADOS: Se evidenció que aún no existe un consenso en su definición, no obstante presenta características reiteradas, como ser un dolor agudo y transitorio, que ocurre posterior a la resolución del bloqueo de nervio periférico. Se describe una incidencia en el ámbito ambulatorio de hasta 50%, pero sin datos fuera de este entorno. Su fisiopatología es compleja y todavía no se comprende en su totalidad, sin embargo, un componente de sensibilización periférica podría determinar una mayor incidencia del fenómeno. Factores de riesgo reconocidos corresponden a cirugías traumatológicas y ortopédicas de miembro superior con bloqueos de nervio periférico densos y pacientes jóvenes de sexo femenino. En relación a su prevención destacan dexametasona y dexmedetomidina como adyuvantes prometedores que junto a un esquema de analgesia multimodal pueden mitigar su aparición. CONCLUSIONES: Entender el impacto del dolor de rebote, sus características, factores de riesgo, medidas preventivas y beneficios de la analgesia multimodal, forma parte de una práctica clínica integral para evitar las consecuencias negativas de una mayor utilización de recursos sanitarios, como también reducir el consumo de opioides y de sus efectos adversos conocidos

Antinociceptive and anxiolytic-like effects of Lavandula angustifolia essential oil on rat models of orofacial pain

Abstract Nociceptive and inflammatory orofacial pain is highly prevalent in the population, which justifies the search for safer analgesics. There is increasing evidence of the analgesic and anxiolytic potential of Lavandula angustifolia essential oil (LAV EO), which may represent, when administered through inhalation, may represent a safer alternative for pain treatment. Objective to evaluate whether LAV EO has antinociceptive effect in the formalin test, and anti-hyperalgesic and anxiolytic-like effects in rats subjected to a model of orofacial postoperative pain. Methodology Female Wistar rats were exposed to LAV EO (5%) by inhalation for 30 minutes. After exposure, animals were injected with formalin (2.5%, 50 μL) or saline into the hind paw or upper lip and the number of flinches or facial grooming time, respectively, were evaluated. Likewise, on day 3 after intraoral mucosa incision, the animals were exposed to LAV EO and facial mechanical, and heat hyperalgesia were assessed. The influence of LAV EO inhalation on anxiety-like behavior was assessed in operated rats by testing them on the open field (OF) and elevated plus maze (EPM). Results LAV EO reduced the phase II of the paw formalin test and both phases of the orofacial formalin test. On day three post-incision, LAV EO reduced heat and mechanical hyperalgesia, from 30 minutes up to three hours, and reduced the anxiety-like behavior in operated rats without causing locomotor deficit. Conclusion LAV EO inhalation results in antinociceptive and anxiolytic-like effects in orofacial pain models, which encourages further studies on LAV EO indications and effectiveness on orofacial pain conditions.

PKCζ-Mitogen-activated protein kinase signaling mediates crotalphine-Induced antinociception / A sinalização da proteína quinase ativada por PKCζ-mitógeno medeia a antinocicepção induzida por crotalfina

Crotalphine (CRP) is a structural analogue to a peptide that was first identified in the crude venom from the South American rattlesnake Crotalus durissus terrificus. This peptide induces a potent and long-lasting antinociceptive effect that is mediated by the activation of peripheral opioid receptors. The opioid receptor activation regulates a variety of intracellular signaling, including the mitogen-activated protein kinase (MAPK) pathway. Using primary cultures of sensory neurons, it was demonstrated that crotalphine increases the level of activated ERK1/2 and JNK-MAPKs and this increase is dependent on the activation of protein kinase Cζ (PKCζ). However, whether PKCζ-MAPK signaling is critical for crotalphine-induced antinociception is unknown. Here, we biochemically demonstrated that the systemic crotalphine activates ERK1/2 and JNK and decreases the phosphorylation of p38 in the lumbar spinal cord. The in vivo pharmacological inhibition of spinal ERK1/2 and JNK, but not of p38, blocks the antinociceptive effect of crotalphine. Of interest, the administration of a PKCζ pseudosubstrate (PKCζ inhibitor) prevents crotalphine-induced ERK activation in the spinal cord, followed by the abolishment of crotalphine-induced analgesia. Together, our results demonstrate that the PKCζ-ERK signaling pathway is involved in crotalphine-induced analgesia. Our study opens a perspective for the PKCζ-MAPK axis as a target for pain control.

Activation of PKCε-ALDH2 axis prevents 4-HNE-induced pain in mice / A ativação do eixo PKCε-ALDH2 previne a dor induzida por 4-HNE em camundongos

Protein kinase Cε (PKCε) is highly expressed in nociceptor neurons and its activation has been reported as pro-nociceptive. Intriguingly, we previously demonstrated that activation of the mitochondrial PKCε substrate aldehyde dehydrogenase-2 (ALDH2) results in anti-nociceptive effects. ALDH2 is a major enzyme responsible for the clearance of 4-hydroxy-2-nonenal (4-HNE), an oxidative stress byproduct accumulated in inflammatory conditions and sufficient to induce pain hypersensitivity in rodents. Here we determined the contribution of the PKCε-ALDH2 axis during 4-HNE-induced mechanical hypersensitivity. Using knockout mice, we demonstrated that PKCε is essential for the nociception recovery during 4-HNE-induced hypersensitivity. We also found that ALDH2 deficient knockin mice display increased 4-HNE-induced nociceptive behavior. As proof of concept, the use of a selective peptide activator of PKCε (ΨεHSP90), which favors PKCε translocation to mitochondria and activation of PKCε-ALDH2 axis, was sufficient to block 4-HNE-induced hypersensitivity in WT, but not in ALDH2-deficient mice. Similarly, ΨεHSP90 administration prevented mechanical hypersensitivity induced by endogenous production of 4-HNE after carrageenan injection. These findings provide evidence that selective activation of mitochondrial PKCε-ALDH2 axis is important to mitigate aldehyde-mediated pain in rodents, suggesting that ΨεHSP90 and small molecules that mimic it may be a potential treatment for patients with pain.

Activation of PKCε-ALDH2 axis prevents 4-HNE-induced pain in mice

Protein kinase Cε (PKCε) is highly expressed in nociceptor neurons and its activation has been reported as pro-nociceptive. Intriguingly, we previously demonstrated that activation of the mitochondrial PKCε substrate aldehyde dehydrogenase-2 (ALDH2) results in anti-nociceptive effects. ALDH2 is a major enzyme responsible for the clearance of 4-hydroxy-2-nonenal (4-HNE), an oxidative stress byproduct accumulated in inflammatory conditions and sufficient to induce pain hypersensitivity in rodents. Here we determined the contribution of the PKCε-ALDH2 axis during 4-HNE-induced mechanical hypersensitivity. Using knockout mice, we demonstrated that PKCε is essential for the nociception recovery during 4-HNE-induced hypersensitivity. We also found that ALDH2 deficient knockin mice display increased 4-HNE-induced nociceptive behavior. As proof of concept, the use of a selective peptide activator of PKCε (ΨεHSP90), which favors PKCε translocation to mitochondria and activation of PKCε-ALDH2 axis, was sufficient to block 4-HNE-induced hypersensitivity in WT, but not in ALDH2-deficient mice. Similarly, ΨεHSP90 administration prevented mechanical hypersensitivity induced by endogenous production of 4-HNE after carrageenan injection. These findings provide evidence that selective activation of mitochondrial PKCε-ALDH2 axis is important to mitigate aldehyde-mediated pain in rodents, suggesting that ΨεHSP90 and small molecules that mimic it may be a potential treatment for patients with pain.

Peripheral mechanisms involved in Tityus bahiensis venom-induced pain

Scorpionism is a public health burden in Brazil. Tityus bahiensis is responsible for most accidents in the Southeastern region of Brazil. Here, the hyperalgesic mechanisms of Tityus bahiensis venom were investigated, focusing on the role of pro-inflammatory cytokines (tumor necrosis factor alpha [TNF-α] and interleukin 1 beta [IL-1β]) and activation of the transcription factor NFκB. Intraplantar (i.pl.) administration of Tityus bahiensis venom (0.2, 0.6, 1.2 and 2.4 μg/20 μL i.pl.) induced mechanical hyperalgesia and thermal hyperalgesia. The 2.4 μg dose of Tityus bahiensis venom induced overt pain-like behavior and increased myeloperoxidase (MPO) and N-acetyl-beta-D-glucosaminidase (NAG) activities, TNF-α and IL-1β levels in the paw tissue. Systemic pre-treatment with etanercept (soluble TNF-α receptor; 10 mg/kg), IL-1ra (IL-1 receptor antagonist; 30 mg/kg) and pyrrolidine dithiocarbamate (PDTC, nuclear factor kappa B [NFκB] inhibitor; 100 mg/kg) inhibited Tityus bahiensis venom-induced mechanical and thermal hyperalgesia, MPO and NAG activity and overt pain-like behavior. These data demonstrate the involvement of TNF-α and IL-1β signaling as well as NFκB activation in Tityus bahiensis venom-induced mechanical and thermal hyperalgesia, overt pain-like behavior, and MPO activity and NAG activity, indicating thus, that targeting these mechanisms might contribute to reducing the pain in this scorpionism.

Intervenção baseada em mindfulness reduz parâmetros de sensibilidade em mulheres com DTM dolorosa crônica / Mindfulness-based intervention reduces sensitivity parameters in women with chronic painful TMD / La intervención basada en la atención plena reduce los parámetros de sensibilidad en mujeres con TMD dolorosa crónica

OBJETIVO: analisar parâmetros clínicos sugestivos de sensibilização central em mulheres com disfunção temporomandibular dolorosa crônica antes e após uma intervenção baseada em mindfulness. MÉTODO: onze mulheres com idade entre 27 e 44 anos (36,36 ± 5,61), com diagnóstico de disfunções temporomandibulares dolorosa crônica (Diagnostic Criteria for Temporomandibular Disorders), participaram do estudo. A hiperalgesia, a alodinia e o limiar de dor à pressão foram avaliados em pontos trigeminais e extra-trigeminais antes e após a intervenção baseada em mindfulness, bem como a aplicação do questionário Mindful Attention Awareness Scale. O programa de mindfulness de 8 semanas foi oferecido às participantes do estudo, com base no protocolo Mindfulness Trainings International, em sessões semanais de 2 horas e uma sessão de 4 horas. RESULTADOS: houve redução significativa da alodinia, da hiperalgesia e aumento do limiar de dor à pressão, além de aumento significativo do nível de atenção plena (p < 0,05) enquanto marcador de efetividade da intervenção baseada em mindfulness oferecida. CONCLUSÃO: índices mais saudáveis nos parâmetros clínicos sugestivos de sensibilização central investigados após a intervenção, representam melhora significativa na relação da pessoa com quadro de enfermidade crônica geradora de experiências desagradáveis contínuas como a disfunções temporomandibulares.

OBJECTIVE: manifestations of allodynia and hyperalgesia are commonly present in chronic painful temporomandibular disorder. Studies point to the benefits of people with chronic pain undergoing mindfulness-based interventions, by demonstrating brain, hormonal, and clinical changes. This study aimed to analyze clinical parameters suggestive of central sensitization (pressure pain threshold, allodynia, and hyperalgesia) in women with chronic painful temporomandibular disorder before and after a mindfulness-based intervention, through a before-and-after intervention study, longitudinal, uncontrolled. METHOD: the analysis included 11 women chosen at random from a total of 20, aged between 27 and 44 years (36.36 ± 5.61), diagnosed with chronic painful temporomandibular disorder according to the Diagnostic Criteria for Temporomandibular Disorders protocol and who completed the 8-week mindfulness-based intervention program. Hyperalgesia, allodynia, and pressure pain threshold were tested at trigeminal and extra-trigeminal points before and after the intervention as well as the application of the questionnaire to measure the level of mindfulness (Mindful Attention Awareness Scale). The 8-week mindfulness program was offered to the study participants, based on the Mindfulness Trainings International - protocol, in weekly 2-hour sessions and a 4-hour session (immersion). RESULTS: the results pointed to a reduction in allodynia, hyperalgesia and an increase in pressure pain threshold, with significant differences in several tested points (p <0.05). The changes identified were accompanied by a significant increase in the level of mindfulness (p < 0.05). CONCLUSION: healthier indexes in clinical parameters suggestive of central sensitization investigated after the intervention represent a significant improvement in the person's relationship with a chronic illness that generates continuous unpleasant experiences such as temporomandibular disorder. Thus, the practice of mindfulness represents an appropriate and particularly interesting care because it is a low-cost, non-invasive intervention with low evidence of adverse effects.

OBJETIVO: las manifestaciones de alodinia y hiperalgesia y están comúnmente presentes en lo trastorno temporomandibular doloroso crónico. Los estudios señalan los beneficios de las personas con dolor crónico que se someten a intervenciones basadas en la atención plena, al demostrar cambios cerebrales, hormonales y clínicos. El objetivo de este estudio fue analizar parámetros clínicos sugestivos de sensibilización central (umbral de dolor por presión, alodinia e hiperalgesia) en mujeres con trastorno temporomandibular doloroso crónico antes y después de una intervención basada en la atención plena, a través de un estudio de intervención antes y después, longitudinal, sin control. MÉTODO: el análisis incluyó a 11 mujeres elegidas al azar de un total de 20, con edades entre 27 y 44 años (36.36 ± 5.61), diagnosticadas con trastorno temporomandibular doloroso crónico de acuerdo con protocolo Criterios de diagnóstico para trastornos temporomandibulares y que completaron el 8- programa de intervención basado en mindfulness de una semana. La hiperalgesia, la alodinia y el umbral de dolor por presión se probaron en los puntos trigémino y extra-trigémino antes y después de la intervención, así como también en la aplicación del cuestionario para medir el nivel de atención plena (Escala de conciencia de atención plena). El programa de atención plena de 8 semanas se ofreció a los participantes del estudio, basado en el protocolo Mindfulness Trainings International, en sesiones semanales de 2 horas y una sesión de 4 horas (inmersión). RESULTADOS: los resultados apuntaron a una reducción en la alodinia, hiperalgesia y un aumento en la umbral de dolor por presión, con diferencias significativas en varios puntos probados (p <0.05). Los cambios identificados fueron acompañados por un aumento significativo en el nivel de atención plena (p <0.05), como un marcador de la efectividad de la capacitación ofrecida para la práctica de la atención plena. CONCLUSIÓN: los índices más saludables en los parámetros clínicos sugestivos de sensibilización central investigados después de la intervención, representan una mejora significativa en la relación de la persona con una enfermedad crónica que genera experiencias continuas desagradables como trastorno temporomandibular doloroso crónico. Por lo tanto, la práctica de la atención plena representa una atención aplicable y particularmente interesante porque es una intervención no invasiva de bajo costo con poca evidencia de efectos adversos.

Evaluation of nociception induced by whole-body vibration remobilization in Wistar rats / Avaliação da nocicepção induzida pela remobilização com vibração de corpo inteiro em ratos Wistar

ABSTRACT BACKGROUND AND OBJECTIVES: The vibrating platform can attenuate the deleterious effects of immobilization related to muscle atrophy. However, there is still a gap regarding the effect of this modality on hyperalgesia related to immobilization. The objective of this study was to analyze the effect of remobilization with whole-body vibration on the nociception of Wistar rats. METHODS: Sixteen rats were randomly distributed into two groups: the FRG group - immobilization and free remobilization and the VPRG - immobilization and remobilization with the vibrating platform. For remobilization with the vibrating platform, the frequency of 60Hz for 10 minutes, five days a week for two weeks was used. The nociception was evaluated on the right paw by a digital analgesiometer, before and at the end of the immobilization, and after two weeks of remobilization. RESULTS: There were differences between evaluations but not between groups, indicating that immobilization reduced the nociceptive threshold and free remobilization, and the remobilization associated with vibration improved the nociceptive threshold compared to the post-immobilization moment. However, they were not able to return to the initial parameters. CONCLUSION: Joint immobilization reduced the nociceptive threshold; however, two weeks of whole-body vibration remobilization were not able to revert the threshold in the immobilized groups.

RESUMO JUSTIFICATIVA E OBJETIVOS: A plataforma vibratória pode atenuar os efeitos deletérios da imobilização relacionados à atrofia muscular, contudo, ainda há uma lacuna com relação ao efeito desta modalidade na hiperalgesia relacionada ao imobilismo. Assim, o objetivo deste estudo foi analisar o efeito da remobilização com plataforma vibratória sobre a nocicepção de ratos Wistar. MÉTODOS: Dezesseis ratos foram distribuídos aleatoriamente no grupo GRL - imobilização e remobilização livre, e no grupo GRPV - imobilização e remobilização com plataforma vibratória. Para a remobilização com plataforma vibratória foi utilizada a frequência de 60Hz, durante 10 minutos, cinco dias por semana, durante duas semanas. A nocicepção foi avaliada na pata direita, por meio de um analgesímetro digital, antes e ao final da imobilização, e após duas semanas de remobilização. RESULTADOS: Houve diferenças entre as avaliações, mas não entre os grupos, indicando que a imobilização reduziu o limiar nociceptivo, e a remobilização livre e associada à vibração melhoraram o limiar nociceptivo comparados com o momento pós-imobilização, no entanto, não foram capazes de retornar aos parâmetros iniciais. CONCLUSÃO: A imobilização articular reduziu o limiar nociceptivo. No entanto, duas semanas de remobilização com a vibração de corpo inteiro não foram capazes de reverter o limiar nos grupos imobilizados.

Effect of environmental enrichment associated or not with physical activity on nociceptive and motor functions in an animal model of fibromyalgia / Efeito do enriquecimento ambiental associado ou não a atividade física nas funções nociceptivas e motoras em um modelo animal de fibromialgia

ABSTRACT BACKGROUND AND OBJECTIVES: Fibromyalgia is a complex syndrome, characterized by chronic widespread musculoskeletal pain and the reduction of physical/functional performance as a major comorbidity. Pharmacological treatment of fibromyalgia has limited effectiveness, making it important to study non-pharmacological therapies, emphasizing physical activity, cognitive behavioral therapy and distracting techniques. Environment enrichment and physical activity have been used in the treatment of diseases associated with increases in peripheral and central nociceptive activity. The objective of this study was the investigation of environmental enrichment, a technique based on physical, sensory and cognitive stimulation, and voluntary physical activity for hyperalgesia prevention in an experimental model of fibromyalgia. METHODS: Twenty-four male Wistar rats were split into four groups: 1. environmental enrichment, 2. physical activity, 3. environmental enrichment plus physical activity and 4. control and kept in these protocols for 4 weeks. Next, diffuse chronic muscle pain was induced by a double injection of acidic saline in the left gastrocnemius muscle. Mechanical paw withdrawal threshold, thermal latency, neuromuscular activity and ambulation in six different moments were assessed: baseline, after the 1st, 2nd, 3rd and 4th weeks and 24 hours after chronic muscle pain induction. RESULTS: Animals kept in the environmental enrichment plus physical activity protocol showed increased mechanical threshold, thermal latency, neuromuscular activity and ambulation even after the acidic saline injections. CONCLUSION: These results suggest association between environmental enrichment and physical activity as a strategy for chronic musculoskeletal pain prevention and physical performance optimization in a diffuse chronic muscle pain model.

RESUMO JUSTIFICATIVA E OBJETIVOS: A fibromialgia é uma síndrome complexa, caracterizada por dor musculoesquelética crônica generalizada, tendo como principal comorbidade a redução do desempenho físico/funcional. O tratamento farmacológico da fibromialgia tem eficácia limitada, tornando importante o estudo de terapias não farmacológicas, enfatizando a atividade física, terapia cognitivo-comportamental e técnicas de distração. O enriquecimento ambiental e a atividade física têm sido utilizados no tratamento de doenças associadas ao aumento da atividade nociceptiva periférica e central. O objetivo deste estudo foi investigar o enriquecimento ambiental, uma técnica baseada na estimulação física, sensorial e cognitiva e atividade física voluntária para prevenção de hiperalgesia em um modelo experimental de fibromialgia. MÉTODOS: Vinte e quatro ratos Wistar machos foram divididos em quatro grupos: 1. enriquecimento ambiental, 2. atividade física, 3. enriquecimento ambiental somado a atividade física e 4. controle, e mantidos nesses protocolos por 4 semanas. A dor muscular crônica difusa foi induzida por uma injeção dupla de salina ácida no músculo gastrocnêmio esquerdo. Foram avaliados o limiar mecânico de retirada da pata, latência térmica, atividade neuromuscular e deambulação em seis momentos diferentes: basal, após a 1ª, 2ª, 3ª e 4ª semanas e 24h após a indução crônica da dor muscular. RESULTADOS: Os animais mantidos no protocolo de enriquecimento ambiental somado a atividade física apresentaram aumento do limiar mecânico, latência térmica, atividade neuromuscular e deambulação mesmo após injeções de salinas ácidas. CONCLUSÃO: Esses resultados sugerem a associação entre enriquecimento ambiental e atividade física como estratégia para prevenção da dor musculoesquelética e déficit motor em modelo de fibromialgia.

Effects of duloxetine, fluoxetine and pregabalin on fentanyl-induced hyperalgesia in rattus novergicus / Efeitos da duloxetina, fluoxetina e pregabalina sobre a hiperalgesia induzida por fentanil em rattus novergicus

ABSTRACT BACKGROUND AND OBJECTIVES: Opioids are drugs used to relieve pain, but may cause increased pain sensitivity, known as opioid-induced hyperalgesia, which adversely affects pain management. This study aimed to check if fentanyl, an opioid widely used in the clinical practice, produces hyperalgesia that can be attenuated by duloxetine, fluoxetine and pregabalin. METHODS: Thirty male Wistar rats were divided into six groups. The animals in group 1 received 1mL of 0.9% saline solution intraperitoneally (IP) and gavage; group 2 received fentanyl at a dose of 100µg.kg-1 IP and 0.9% saline solution per gavage; groups 3, 4 and 5 received fentanyl at the dose of 100µg.kg-1 IP, and gavage with duloxetine, 40mg.kg-1, fluoxetine, 40mg.kg-1 and pregabalin, 40mg.kg-1, respectively. Under general anesthesia with isoflurane, all animals were submitted to plantar surgical incision. The application of Von Frey filaments assessed hyperalgesia at the second hour, one, three, five and seven days after treatment. RESULTS: Two hours after the procedure, no differences were observed between G1 and G2, although G3, G4, and G5 showed less hyperalgesia. On day one and day three, a greater hyperalgesic effect was observed in G2 when compared to G1, G3, G4 and G5. On day five, there was a hyperalgesic effect on G2, and on day seven, there were no differences among the groups. CONCLUSION: The results suggest that fentanyl induces hyperalgesia and the efficacy of duloxetine, fluoxetine, and pregabalin in reducing it.

RESUMO JUSTIFICATIVA E OBJETIVOS: Opioides são fármacos utilizados para o alívio da dor, porém, podem causar aumento da sensibilidade dolorosa, denominada hiperalgesia induzida por opioides, que afeta negativamente o tratamento da dor. O objetivo deste estudo foi avaliar se o fentanil, opioide amplamente utilizado na prática clínica, produz hiperalgesia que pode ser atenuada pela duloxetina, fluoxetina e pregabalina. MÉTODOS: Trinta ratos Wistar machos, foram divididos em 6 grupos. No grupo 1, os animais receberam 1mL de solução fisiológica (SF) a 0,9% por via intraperitoneal (IP) e por gavagem; no grupo 2, fentanil na dose de 100µg.kg-1 IP e SF a 0,9% por gavagem; nos grupos 3, 4 e 5 os animais receberam fentanil na dose de 100µg.kg-1 IP e, por gavagem, receberam respectivamente duloxetina, 40mg.kg-1, fluoxetina, 40mg.kg-1 e pregabalina, 40mg.kg-1. A avaliação da hiperalgesia e sua atenuação foi feita pela aplicação de filamentos de Von Frey, na 2ª hora e nos dias 1, 3, 5 e 7, após o tratamento. RESULTADOS: Na 2ª hora pós-procedimento não foram observadas diferenças entre G1 e G2, entretanto, G3, G4 e G5 se mostraram com menor hiperalgesia. No 1º e 3º dias foi observado maior efeito hiperalgésico em G2 quando comparado com G1, G3, G4 e G5. No 5º dia foi observado efeito hiperalgésico no G2, e no 7º dia não houve diferenças entre os grupos. CONCLUSÃO: Os resultados sugerem que o fentanil induz hiperalgesia e eficácia da duloxetina, fluoxetina e pregabalina na sua redução.

Avaliação da eficácia de diferentes protocolos de analgesia preemptiva em cirurgias odontológicas / Evaluation of the effectiveness of different preemptive analgesia protocols in dental surgery

A analgesia preemptiva tem como princípio a administração de fármacos antes do início dos estímulos dolorosos, a fim de reduzir ou prevenir a dor pós-operatória. Apesar da sua importância, os efeitos da analgesia preemptiva em cirurgias odontológicas reportados na literatura ainda são conflitantes. Assim, o objetivo deste estudo foi avaliar a eficácia clínica de diferentes classes de medicamentos para analgesia preemptiva, em 2 propostas de investigação 1) cirurgias para exodontia de terceiros molares impactados; 2) cirurgias periodontais a retalho. Para tal, foram realizados ensaios clínicos randomizados placebo-controlados onde os participantes recebiam, 1 hora antes da cirurgia, o medicamento teste e o placebo em cirurgias distintas, em um desenho boca-dividida. Na primeira proposta de investigação, de um total de 376 pacientes com necessidade de exodontia de terceiros molares inferiores classe IIB, foram selecionados 100 pacientes, com idade entre 18 - 30 anos (22,4±2,9), alocados em 5 grupos (n = 20 por grupo), sendo: 1) paracetamol; 2) cetoprofeno; 3) ibuprofeno; 4) nimesulida; 5) dexametasona). Através de escala visual analógica, dor pós-operatória foi avaliada nos tempos 1h, 6h, 12h, 24h, 48h e 72h e edema foi avaliado nos tempos baseline, 24h, 48h, 72h e 7 dias pós-operatórias. As diferenças entre o medicamento de teste e o placebo foram determinadas como a variável de resposta. Um modelo de Equação de Estimativa Generalizada foi ajustado para cada variável desfecho e os grupos foram comparados pelo teste de Tukey. O ibuprofeno e a nimesulida apresentaram efeitos preemptivos gerais mais altos no controle de dor ao longo do tempo, sem diferenças entre eles (p = 0,557). O paracetamol mostrou efeitos gerais mais baixos no controle do edema ao longo do tempo, quando comparado aos outros medicamentos em teste, que mostraram efeitos semelhantes (p<0,05). Também foram observados melhores resultados na quantidade de medicamentos de resgate para o ibuprofeno e a nimesulida, sem diferenças entre eles (p = 0,999). Ibuprofeno e a nimesulida mostraram melhores efeitos preemptivos gerais nas cirurgias de terceiros molares inferiores impactados e assim devem ser considerados caso a caso como medicamentos de escolha em analgesia preemptiva. Na segunda proposta de investigação, de um total de 360 indivíduos com necessidade de cirurgias a retalho, foram selecionados 40 pacientes, com idade entre 18 a 60 anos (43,40 ± 11,91), alocados em 2 grupos (n = 20 por grupo), sendo 1) ibuprofeno; 2) nimesulida. Através da escala visual analógica, dor pós-operatória foi avaliada nos tempos 1h, 6h, 12h, 24h, 48h e 72h. As diferenças entre medicamento teste e placebo foram determinadas como a variável de resposta. Um modelo de Equação de Estimativa Generalizada separado foi ajustado para cada variável desfecho e os grupos foram comparados pelo teste de Tukey. O uso de medicação de resgate foi menor e o tempo pós-operatório foi maior nos grupos teste ibuprofeno e nimesulida em comparação ao placebo (p<0,001). E o grupo nimesulida apresentou escores de EVA mais baixos nos tempos T12, T24, T72 horas (p<0,001; p<0,001; p<0,007), mostrando-se um coadjuvante benéfico para o controle da dor pós-operatória em cirurgias periodontais a retalho.

Preemptive analgesia has as its principle the administration of drugs before the start of painful stimuli, in order to reduce or prevent postoperative pain. Despite its importance, the effects of preemptive analgesia in dental surgeries reported in the literature are still conflicting. Thus, the objective of this study was to evaluate the clinical efficacy of different classes of drugs for preemptive analgesia, in 2 different research proposals: 1) surgeries for extraction of impacted third molars; 2) periodontal flap surgeries. To this end, randomized placebo-controlled clinical trials were carried out where the participants received, 1 hour before surgery, the test drug and the placebo in different surgeries, in a mouth-divided design. In the first research proposal, from a total of 376 patients in need of extraction of lower third molars, class IIB, 100 patients were selected, aged between 18 - 30 years (22.4 ± 2.9), allocated in 5 groups ( n = 20 per group), being: 1) acetaminophen; 2) ketoprofen; 3) ibuprofen; 4) nimesulide; 5) dexamethasone). Through a visual analog scale, postoperative pain was assessed at 1h, 6h, 12h, 24h, 48h and 72h and edema was assessed at baseline, 24h, 48h, 72h and 7 postoperative days. Differences between test drug and placebo were determined as response variable. A separate Generalized Estimation Equation model was separated for each outcome variable and the groups were compared using the Tukey test. Ibuprofen and nimesulide higher overall preemptive sinks in pain controls over time, with no differences between them (p = 0.557). Paracetamol general effects resulting from lower control of edema over time, when compared to other drugs under test, which affect other similar effects (p <0.05). Better results were also observed in the quantity of rescue drugs for ibuprofen and nimesulide, with no differences between them (p = 0.999). It was concluded that ibuprofen and nimesulide are the main general preemptive effects in impacted lower third molar surgeries. Thus, in the decision-making process for preemptive analgesia, ibuprofen and nimesulide should be considered case by case as the drugs of choice. In the second research proposal, from a total of 360 individuals in need of retail surgery, 40 patients were selected, aged between 18 and 60 years (43.40 ± 11.91) years, allocated in 2 groups (n = 20 per group), being 1) ibuprofen; 2) nimesulide. Through the visual analog scale, postoperative pain was assessed at 1h, 6h, 12h, 24h, 48h and 72h. The differences between the test drug and the placebo were determined as the response variable. A separate Generalized Estimation Equation model was separated for each outcome variable and the groups were compared using the Tukey test. The nimesulide group had lower complementary EVA scores at times T12, T24, T72 hours (p <0.001; p <0.001; p <0.007). The use of rescue medication was less secondary and the postoperative time was longer in the ibuprofen and nimesulide test groups compared to placebo (p <0.001). Thus, nimesulide can be considered a beneficial adjunct to the control of postoperative pain in periodontal flap surgeries.

Efecto del fentanilo intratecal en hiperlagesia secundaria posoperatoria de cirugía ligamento cruzado anterior de rodilla / Effect of Intrathecal fentanyl on secondary hyperalgesia, in patients undergoing anterior cruciate ligament repair

BACKGROUND AND OBJECTIVES: Fentanyl addition is a common practice when administering spinal anesthesia. Intrathecal fentanyl has been associated to increased postoperative pain and increase morphine consumption, but considered to be related to acute opioid tolerance. This prospective, randomized, blind study evaluates the effect of intrathecal fentanyl in the development of secondary hyperalgesia, measured with Von Frey filaments, in patients undergoing anterior cruciate ligament repair. METHODS: 46 patients having anterior cruciate ligament repair, received intrathecal hyperbaric bupivacaine 13.5 mg with fentanyl 20 mcg or no fentanyl addition. Light touch pain threshold was measured with von Frey filaments before anesthesia, at 6 and 24 hours post anesthesia in the non-operated thigh and in the forearm. Visual analogue pain scores and morphine consumption were also measured at the same time. RESULTS: Baseline thresholds to mechanical stimuli were similar in both groups. In the forearm, analysis showed a decreased threshold for the non-fentanyl group at 24 h p = 0.036. In the lower extremity, control and treatment group showed lower thresholds (secondary hyperalgesia) p = 0.002 but no difference between them p = 0.795. VAS score and morphine consumption did not differ among groups. CONCLUSIONS: Spinal fentanyl added to hyperbaric bupivacaine showed no evidence of an augmented state of hyperalgesia after ACL repair, neither by pain threshold modification nor clinical outcomes. On the contrary, at 24 h, fentanyl may have a protective effect at levels above the spinal block.

ANTECEDENTES Y OBJETIVOS: El uso de fentanilo es una práctica común en la administración de anestesia espinal. Su aplicación se ha asociado a un aumento del dolor post operatorio y a un aumento en el uso de morfina; por otro lado, se ha vinculado a una tolerancia aguda a opioides. El siguiente estudio prospectivo, randomizado y ciego, evalúa los efectos del fentanilo intratecal en la aparición de hiperalgesia secundaria, medida a través de filamentos Von Frey, en pacientes operados de ligamento cruzado anterior. METODOLOGÍA: Se incluyeron a 46 pacientes operados de ligamento cruzado anterior (LCA) con una dosis intratecal de bupivacaína hiperbárica de 13,5 mg; con y sin la adición de fentanilo de 20 mcg. Se midió el umbral del dolor mecánico, a través de filamentos Von Frey, antes de la anestesia, a las 6 y 24 horas postanestesia en el muslo no operado y en el antebrazo. Al mismo tiempo, se midió la puntuación del dolor en la escala verbal numérica (EVN) y el consumo de morfina. RESULTADOS: Los umbrales basales ante la estimulación mecánica resultaron similares en ambos grupos. En el antebrazo, el análisis mostró una disminución del umbral en el grupo de pacientes sin fentanilo, a las 24 h, p = 0,036 comparado con uso de fentanilo. En el muslo, el grupo control y tratamiento mostró umbrales más bajos (hiperalgesia secundaria) p = 0,002; no obstante, no se mostraron diferencias entre ellos. No se mostraron diferencias entre las puntuaciones de la EVN y el consumo de morfina en los dos grupos. CONCLUSIÓN: No hay evidencia que la adición de fentanilo espinal, a la dosis de bupivacaína hiperbárica, haya contribuido a un aumento en la hiperalgesia tras la reparación del LCA, medido por la modificación del umbral del dolor, ni en los resultados clínicos. Al contrario a las 24 h fentanilo puede tener un efecto protector de la hiperalgesia secundaria sobre el nivel del bloqueo espinal.