RESUMO
Activation of neurons and glial cells in the dorsal root ganglion is one of the key mechanisms for the development of hyperalgesia. The aim of the present study was to examine the role of neuroglial activity in the development of opioid-induced hyperalgesia. Male rats were treated with morphine daily for 3 days. The resultant phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 in the dorsal root ganglion was analyzed by immunohistochemistry and Western blotting. Pain hypersensitivity was analyzed using behavioral studies. The amount of cytokine expression in the dorsal root ganglion was also analyzed. Repeated morphine treatment induced hyperalgesia and marked induction of phosphorylated ERK1/2 in the neurons and satellite glial cells on day 3. An opioid receptor antagonist, toll like receptor-4 inhibitor, MAP/ERK kinase (MEK) inhibitor and gap junction inhibitor inhibited morphine-induced hyperalgesia and ERK1/2 phosphorylation. Morphine treatment induced alteration of cytokine expression, which was inhibited by the opioid receptor antagonist, toll like receptor-4 inhibitor, MEK inhibitor and gap junction inhibitor. Dexamethasone inhibited morphine-induced hyperalgesia and ERK1/2 phosphorylation after morphine treatment. The peripherally restricted opioid receptor antagonist, methylnaltrexone, inhibited hyperalgesia and ERK1/2 phosphorylation. Morphine activates ERK1/2 in neurons and satellite glial cells in the dorsal root ganglion via the opioid receptor and toll like receptor-4. ERK1/2 phosphorylation is gap junction-dependent and is associated with the alteration of cytokine expression. Inhibition of neuroinflammation by activation of neurons and glia might be a promising target to prevent opioid-induced hyperalgesia.
RESUMO
Little is known about the functional relationship between endoplasmic reticulum (ER) stress and development of pain hypersensitivity after nerve injury. The aim of this study was to investigate the role of ER stress in the development of pain hypersensitivity in the dorsal root ganglion (DRG) after spinal nerve ligation (SNL). SNL was performed in male Sprague-Dawley rats. Real-time PCR and immunohistochemistry were performed to investigate ER stress markers including glucose-regulated protein (GRP) 78, C/EBP homologous protein (CHOP), and spliced form of the X-box binding protein 1 (sXBP1) in L4 and L5 DRG. Behavioral assessment with von Frey filaments, radiant heat, and acetone stimulation was performed to investigate pain hypersensitivity. The ER stress inhibitor salubrinal was administered prior to and 1, 3, and 5â¯days after SNL treatment. Separately, the ER stress inducer tunicamycin was applied to L5 DRG. GRP78, CHOP, and sXBP1 mRNA and protein expression in L5 DRG was increased 1 and 3â¯days after SNL but returned to baseline 7â¯days after SNL. In L4 DRG, ER stress markers showed no remarkable change. Immunohistochemistry demonstrated that GRP78 expression was detected in the majority of DRG neurons and in satellite glial cells. Treatment with salubrinal inhibited CHOP expression in L5 DRG and alleviated pain hypersensitivity for 5â¯days after SNL. Tunicamycin induced ER stress in the DRG and pain hypersensitivity 2â¯h after treatment. These results demonstrated that ER stress is induced in the injured DRG and contributes to the development of pain hypersensitivity after nerve injury.
Assuntos
Estresse do Retículo Endoplasmático , Gânglios Espinais/metabolismo , Hiperalgesia/metabolismo , Traumatismos dos Nervos Periféricos/metabolismo , Animais , Expressão Gênica , Hiperalgesia/etiologia , Masculino , Limiar da Dor , Traumatismos dos Nervos Periféricos/complicações , Ratos Sprague-Dawley , Células Receptoras Sensoriais/metabolismoRESUMO
PURPOSE: Predictive value and accuracy of the acute pain trajectory were compared with those of pain intensity at 1 day after the surgery for pain prevalence at 6 months after the surgery. MATERIALS AND METHODS: Female patients scheduled for breast cancer surgery were eligible for this study. Patients were questioned about pain intensity daily during the 7 days after surgery. Presence of pain, its location, and intensity as well as the Japanese version of the quality of the recovery-40 (QOR-40) were determined in an interview prior to and at 6 months after the surgery. Acute pain trajectory was determined by a group-based trajectory modeling analysis that was based on the pain intensity at 1-7 days after surgery. Predictive value of the acute pain trajectory for the presence of pain at 6 months after the surgery was assessed by a logistic regression model. The predictive value was compared with pain intensity at 1 day after the surgery. RESULTS: A total of 123 participants completed the 6-month follow-up. The three-cluster model (mild, moderate, and severe pain) was considered to be the most statistically appropriate model for the acute pain trajectory. After 6 months, 51.2% and 8.9% of participants reported pain and severe pain, respectively. Presence of pain at 6 months after the surgery was associated with poor recovery. The severe pain cluster was significantly associated with the presence of pain at 6 months after the surgery (adjusted odds ratio, 9.40; P<0.001 vs mild pain cluster). CONCLUSION: Classification of patients according to the acute pain trajectory, when compared with the classification according to pain intensity at 1 day after the surgery, made it possible to predict with better precision those patients who will develop persistent postsurgical pain.
RESUMO
Background Intense nociceptive signaling arising from ongoing injury activates primary afferent nociceptive systems to generate peripheral sensitization. ERK1/2 phosphorylation in dorsal root ganglion can be used to visualize intracellular signal activity immediately after noxious stimulation. The aim of this study was to investigate spatiotemporal characteristics of ERK1/2 phosphorylation against tissue injury in the primary afferent neurons. Methods Plantar incisions were made in the hind paws of Sprague-Dawley rats (n =150). Levobupivacaine was injected into the plantar aspect of the paws and ankles, Mitogen-activated protein kinase kinase (MEK) inhibitor was injected into the paw, and carbenoxolone, dual inhibitor of the gap junction and pannexin channel, was intraperitoneally injected. Pain hypersensitivity was investigated by a behavioral study, while phosphorylated ERK1/2 was detected in dorsal root ganglion and hind paw using immunohistochemistry and Western blot. Results Phosphorylated ERK1/2 was induced in dorsal root ganglion (26.8 ± 2.9% at baseline, 65.6 ± 3.6% at 2 min, and 26.3 ± 3.4% at 2 h) after the incision. NF-200 positive A-fiber neurons and satellite glial cells were positive for phosphorylated ERK1/2. Injury-induced pain hypersensitivity was abolished by MEK inhibitor. Levobupivacaine treatment inhibited phosphorylated ERK1/2 induction, carbenoxolone treatment inhibited glial phosphorylated ERK1/2 at 2 min after the injury, and carbenoxolone inhibited pain hypersensitivity and neuronal phosphorylated ERK1/2 at 1 h after the injury. Conclusion ERK1/2 phosphorylation in A-fiber neurons and satellite glial cells immediately after injury contributes to the generation of pain hypersensitivity. Signal communication between neurons and satellite glial cells expands the duration of neuronal ERK1/2 phosphorylation and pain hypersensitivity at 1 h after tissue injury.
Assuntos
MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Extremidades/patologia , Gânglios Espinais/enzimologia , Gânglios Espinais/patologia , Neuroglia/enzimologia , Neurônios/enzimologia , Dor/enzimologia , Analgésicos/farmacologia , Animais , Bupivacaína/farmacologia , Bupivacaína/uso terapêutico , Ativação Enzimática , Extremidades/cirurgia , Hipersensibilidade/enzimologia , Hipersensibilidade/patologia , Masculino , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Dor/tratamento farmacológico , Dor/patologia , Inibidores de Proteínas Quinases/farmacologia , Ratos Sprague-DawleyRESUMO
Following tissue injury, phosphorylation of p38 MAPK in the primary afferent neurons drives sensitization of peripheral nerve. Dexmedetomidine extends the duration of reginal analgesia by local anesthetics. The effect of regional analgesia on the peripheral nerve sensitization is not known. The aim of this study is to investigate the effect of regional analgesia by levobupivacaine with or without dexmedetomidine on the p38 MAPK phosphorylation in the dorsal root ganglion (DRG) and inflammatory reaction in the peripheral tissue. A plantar incision was made in the hind paws of Sprague-Dawley rats. Prior to incision, levobupivacaine with or without dexmedetomidine was injected to the plantar aspect of the paws and ankles. A behavioral study was performed to investigate pain hypersensitivity. Phosphorylation of p38 MAPK in the DRG was assessed by immunohistochemistry and Western blotting. Macrophage accumulation, NGF, and TNF-α in the DRG and plantar tissue were measured using immunohistochemistry, real-time PCR and ELISA. Pain hypersensitivity was induced immediately after the plantar incision. Treatment with levobupivacaine inhibited the development of pain hypersensitivity for two hours. Adjunctive dexmedetomidine extended the anti-hyperalgesic duration for four hours. Levobupivacaine without dexmedetomidine could not inhibit p38 MAPK phosphorylation in the DRG completely. However, Levobupivacaine and dexmedetomidine completely inhibited p38 MAPK phosphorylation, and reduced macrophage accumulation and TNF-α amount in the plantar tissue. Inhibition of p38 MAPK phosphorylation via TNF-α suggests dexmedetomidine has a peripheral mechanism of anti-inflammatory action when used asan adjunct to local anesthetics, and provides a molecular basis for the prevention of peripheral sensitization following surgery.
Assuntos
Bupivacaína/análogos & derivados , Dexmedetomidina/farmacologia , Gânglios Espinais/efeitos dos fármacos , Neurônios Aferentes/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Bupivacaína/farmacologia , Gânglios Espinais/metabolismo , Inflamação/tratamento farmacológico , Levobupivacaína , Masculino , Dor , Manejo da Dor/métodos , Fosforilação , Ratos Sprague-DawleyRESUMO
BACKGROUND: Subglottic stenosis can lead to life-threatening difficult tracheal intubation during general anesthesia. We report a case of difficult tracheal intubation in an 11-month-old female who had unrecognized subglottic stenosis. CASE PRESENTATION: The patient was scheduled for elective correction of a right accessory auricle. She was suspected of having first and second branchial arch syndrome. Preoperative physical examination was normal. Anesthesia was induced uneventfully using sevoflurane. It was not possible to pass size 4.0, 3.5, or 3.0 cuffed endotracheal tubes due to an advanced subglottic lesion. Subsequent successful intubation was achieved using a 3.0 uncuffed tube. Stridor was audible after extubation, and the patient required several days' treatment with dexamethasone to address respiratory distress. CONCLUSIONS: We encountered unrecognized subglottic stenosis that led to difficult tracheal intubation and post-extubation airway stenosis.
RESUMO
Regional analgesia, opioids, and several oral analgesics are commonly used for the treatment of acute pain after breast cancer surgery. While all of these treatments can suppress the acute postsurgical pain, there is growing evidence that suggests that the postsurgical comorbidity will differ in accordance with the type of analgesic used during the surgery. Our current study reviewed the effect of analgesics used for acute pain treatments on the major comorbidities that occur after breast cancer surgery. A considerable number of clinical studies have been performed to investigate the relationship between the acute analgesic regimen and common comorbidities, including inadequate quality of recovery after the surgery, persistent postsurgical pain, and cancer recurrence. Previous studies have shown that the choice of the analgesic modality does affect the postsurgical comorbidity. In general, the use of regional analgesics has a beneficial effect on the occurrence of comorbidity. In order to determine the best analgesic choice after breast cancer surgery, prospective studies that are based on a clear definition of the comorbidity state will need to be undertaken in the future.