Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Resultados 1 - 20 de 42
Filtrar
1.
Anesth Analg ; 129(5): 1414-1421, 2019 11.
Artículo en Inglés | MEDLINE | ID: mdl-30044299

RESUMEN

BACKGROUND: A major advancement in the field of analgesic pharmacology has been the development of G-protein-biased opioid agonists that display less respiratory depression than conventional drugs. It is uncertain, however, whether these new drugs cause less tolerance, hyperalgesia, and other maladaptations when administered repeatedly. METHODS: The archetypical µ-opioid receptor agonist morphine and, separately, the G-protein-biased µ-opioid receptor agonist oliceridine were administered to mice. These drugs were used in models of acute analgesia, analgesic tolerance, opioid-induced hyperalgesia, reward, and physical dependence. In addition, morphine and oliceridine were administered for 7 days after tibia fracture and pinning; mechanical allodynia and gait were followed for 3 weeks. Finally, the expression of toll-like receptor-4 and nacht domain-, leucine-rich repeat-, and pyrin domain-containing protein 3 (NALP3) and interleukin-1ß mRNA were quantified in spinal tissue to measure surgical and drug effects on glia-related gene expression. RESULTS: We observed using the tail flick assay that oliceridine was a 4-fold more potent analgesic than morphine, but that oliceridine treatment caused less tolerance and opioid-induced hyperalgesia than morphine after 4 days of ascending-dose administration. Using similar analgesic doses, morphine caused reward behavior in the conditioned place preference assay while oliceridine did not. Physical dependence was, however, similar for the 2 drugs. Likewise, morphine appeared to more significantly impair the recovery of nociceptive sensitization and gait after tibial fracture and pinning than oliceridine. Furthermore, spinal cord toll-like receptor-4 levels 3 weeks after fracture were higher in fracture mice given morphine than those given oliceridine. CONCLUSIONS: Aside from reduced respiratory depression, G-protein-biased agonists such as oliceridine may reduce opioid maladaptations and enhance the quality of surgical recovery.


Asunto(s)
Receptores Opioides mu/agonistas , Compuestos de Espiro/farmacología , Tiofenos/farmacología , Analgésicos Opioides/farmacología , Animales , Relación Dosis-Respuesta a Droga , Ligandos , Masculino , Ratones , Ratones Endogámicos C57BL , Morfina/farmacología , Dolor Postoperatorio/tratamiento farmacológico , Fracturas de la Tibia/fisiopatología , Receptor Toll-Like 4/análisis
2.
Mol Pain ; 13: 1744806917730212, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28845733

RESUMEN

Abstract: Chronic pain after traumatic brain injury (TBI) is very common, but the mechanisms linking TBI to pain and the pain-related interactions of TBI with peripheral injuries are poorly understood. Chemokine receptors play an important role in both pain and brain injury. In the current work, we pursued the hypothesis that the epigenetically regulated CXC chemokine receptor 2 (CXCR2) is a crucial modulator of nociceptive sensitization induced by TBI. For these studies, we used the rat lateral fluid percussion model of TBI. Histone actyltransferase activity was blocked using anacardic acid beginning immediately following injury, or delayed for seven days prior to administration. The selective CXCR2 antagonist SCH527123 administered systemically or intrathecally was used to probe the role of chemokine signaling on mechanical hindpaw sensitization after TBI. The expression of the CXCR2 receptor was accomplished using real-time PCR, immunohistochemistry, and Western blotting, while epigenetic regulation was assessed using chromatin immunoprecipitation assay. The spinal levels of several pain-related mediators including CXCL1, an endogenous ligand for CXCR2, as well as brain-derived neurotrophic factor and prodynorphin were measured by enzyme-linked immunosorbent assay. We observed that anacardic acid potently blocked and reversed mechanical hindpaw sensitization after TBI. The same drug was able to prevent the upregulation of CXCR2 after TBI, but did not affect the spinal expression of other pain mediators. On the other hand, both systemically and intrathecally administered SCH527123 reversed hindpaw allodynia after TBI. Most of the spinal CXCR2 appeared to be expressed by spinal cord neurons. Chromatin immunoprecipitation experiments demonstrated TBI-enhanced association of the CXCR2 promoter with acetylated-H3K9 histone protein that was also reversible using anacardic acid. Taken together, our findings suggested that TBI causes the upregulation of spinal CXCR2 through an epigenetic mechanism ultimately supporting nociceptive sensitization. The use of CXCR2 antagonists may, therefore, be useful in pain resulting from TBI.


Asunto(s)
Benzamidas/farmacología , Lesiones Traumáticas del Encéfalo/metabolismo , Ciclobutanos/farmacología , Hiperalgesia/metabolismo , Receptores de Interleucina-8B/metabolismo , Ácidos Anacárdicos/farmacología , Animales , Lesiones Traumáticas del Encéfalo/complicaciones , Quimiocina CXCL1/metabolismo , Modelos Animales de Enfermedad , Hiperalgesia/tratamiento farmacológico , Masculino , Ratas Sprague-Dawley , Receptores de Interleucina-8B/efectos de los fármacos , Médula Espinal/metabolismo , Regulación hacia Arriba
3.
BMC Genomics ; 17: 313, 2016 Apr 29.
Artículo en Inglés | MEDLINE | ID: mdl-27129385

RESUMEN

BACKGROUND: Opioids are a mainstay for the treatment of chronic pain. Unfortunately, therapy-limiting maladaptations such as loss of treatment effect (tolerance), and paradoxical opioid-induced hyperalgesia (OIH) can occur. The objective of this study was to identify genes responsible for opioid tolerance and OIH. RESULTS: These studies used a well-established model of ascending morphine administration to induce tolerance, OIH and other opioid maladaptations in 23 strains of inbred mice. Genome-wide computational genetic mapping was then applied to the data in combination with a false discovery rate filter. Transgenic mice, gene expression experiments and immunoprecipitation assays were used to confirm the functional roles of the most strongly linked gene. The behavioral data processed using computational genetic mapping and false discovery rate filtering provided several strongly linked biologically plausible gene associations. The strongest of these was the highly polymorphic Mpdz gene coding for the post-synaptic scaffolding protein Mpdz/MUPP1. Heterozygous Mpdz +/- mice displayed reduced opioid tolerance and OIH. Mpdz gene expression and Mpdz/MUPP1 protein levels were lower in the spinal cords of low-adapting 129S1/Svlm mice than in high-adapting C57BL/6 mice. Morphine did not alter Mpdz expression levels. In addition, association of Mpdz/MUPP1 with its known binding partner CaMKII did not differ between these high- and low-adapting strains. CONCLUSIONS: The degrees of maladaptive changes in response to repeated administration of morphine vary greatly across inbred strains of mice. Variants of the multiple PDZ domain gene Mpdz may contribute to the observed inter-strain variability in tolerance and OIH by virtue of changes in the level of their expression.


Asunto(s)
Proteínas Portadoras/genética , Tolerancia a Medicamentos/genética , Hiperalgesia/genética , Morfina/efectos adversos , Dominios PDZ , Analgésicos Opioides/efectos adversos , Animales , Mapeo Cromosómico , Relación Dosis-Respuesta a Droga , Técnicas de Silenciamiento del Gen , Haplotipos , Hiperalgesia/inducido químicamente , Masculino , Proteínas de la Membrana , Ratones Endogámicos , Ratones Transgénicos , Dependencia de Morfina/genética , Polimorfismo de Nucleótido Simple
4.
Mol Pain ; 122016.
Artículo en Inglés | MEDLINE | ID: mdl-27094549

RESUMEN

BACKGROUND: Opioids have become the mainstay for treatment of moderate to severe pain and are commonly used to treat surgical pain. While opioid administration has been shown to cause opioid-induced hyperalgesia and tolerance, interactions between opioid administration and surgery with respect to these problematic adaptations have scarcely been addressed. Accumulating evidence suggests opioids and nociceptive signaling may converge on epigenetic mechanisms in spinal cord to enhance or prolong neuroplastic changes. Epigenetic regulation of Bdnf (brain-derived neurotrophic factor) and Pdyn (prodynorphin) genes may be involved. RESULTS: Four days of ascending doses of morphine treatment caused opioid-induced hyperalgesia and reduced opioid analgesic efficacy in mice. Both opioid-induced hyperalgesia and the reduced opioid analgesic efficacy were enhanced in mice that received hindpaw incisions. The expression of Bdnf and Pdyn (qPCR) was increased after morphine treatment and incision. Chromatin immunoprecipitation assays demonstrated that the Pdyn and Bdnf promoters were more strongly associated with acetylated H3K9 after morphine plus incision than in the morphine or incision alone groups. Selective tropomyosin-related kinase B (ANA-12) and κ-opioid receptor (nor-binaltorphimine) antagonists were administered intrathecally, both reduced hyperalgesia one or three days after surgery. Administration of ANA-12 or nor-binaltorphimine attenuated the decreased morphine analgesic efficacy on day 1, but only nor-binaltorphimine was effective on day 3 after incision in opioid-exposed group. Coadministration of histone acetyltransferase inhibitor anacardic acid daily with morphine blocked the development of opioid-induced hyperalgesia and attenuated incision-enhanced hyperalgesia in morphine-treated mice. Anacardic acid had similar effects on analgesic tolerance, showing the involvement of histone acetylation in the interactions detected. CONCLUSIONS: Spinal epigenetic changes involving Bdnf and Pdyn may contribute to the enhanced postoperative nociceptive sensitization and analgesic tolerance observed after continuous opioid exposure. Treatments blocking the epigenetically mediated up-regulation of these genes or administration of TrkB or κ-opioid receptor antagonists may improve the clinical utility of opioids, particularly after surgery.


Asunto(s)
Analgésicos Opioides/uso terapéutico , Analgésicos/uso terapéutico , Tolerancia a Medicamentos , Epigénesis Genética/efectos de los fármacos , Dolor Postoperatorio/tratamiento farmacológico , Dolor Postoperatorio/genética , Médula Espinal/metabolismo , Analgésicos/farmacología , Analgésicos Opioides/farmacología , Animales , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Dinorfinas/metabolismo , Histona Acetiltransferasas/antagonistas & inhibidores , Histona Acetiltransferasas/metabolismo , Hiperalgesia/complicaciones , Hiperalgesia/genética , Hiperalgesia/patología , Masculino , Ratones Endogámicos C57BL , Morfina/administración & dosificación , Morfina/farmacología , Transducción de Señal/efectos de los fármacos , Médula Espinal/efectos de los fármacos , Médula Espinal/cirugía
5.
BMC Genomics ; 15: 345, 2014 May 08.
Artículo en Inglés | MEDLINE | ID: mdl-24884839

RESUMEN

BACKGROUND: Opioids are the cornerstone of treatment for moderate to severe pain, but chronic use leads to maladaptations that include: tolerance, dependence and opioid-induced hyperalgesia (OIH). These responses limit the utility of opioids, as well as our ability to control chronic pain. Despite decades of research, we have no therapies or proven strategies to overcome this problem. However, murine haplotype based computational genetic mapping and a SNP data base generated from analysis of whole-genome sequence data (whole-genome HBCGM), provides a hypothesis-free method for discovering novel genes affecting opioid maladaptive responses. RESULTS: Whole genome-HBCGM was used to analyze phenotypic data on morphine-induced tolerance, dependence and hyperalgesia obtained from 23 inbred strains. The robustness of the genetic mapping results was analyzed using strain subsets. In addition, the results of analyzing all of the opioid-related traits together were examined. To characterize the functional role of the leading candidate gene, we analyzed transgenic animals, mRNA and protein expression in behaviorally divergent mouse strains, and immunohistochemistry in spinal cord tissue. Our mapping procedure identified the allelic pattern within the netrin-1 receptor gene (Dcc) as most robustly associated with OIH, and it was also strongly associated with the combination of the other maladaptive opioid traits analyzed. Adult mice heterozygous for the Dcc gene had significantly less tendency to develop OIH, become tolerant or show evidence of dependence after chronic exposure to morphine. The difference in opiate responses was shown not to be due to basal or morphine-stimulated differences in the level of Dcc expression in spinal cord tissue, and was not associated with nociceptive neurochemical or anatomical alterations in the spinal cord or dorsal root ganglia in adult animals. CONCLUSIONS: Whole-genome HBCGM is a powerful tool for identifying genes affecting biomedical traits such as opioid maladaptations. We demonstrate that Dcc affects tolerance, dependence and OIH after chronic opioid exposure, though not through simple differences in expression in the adult spinal cord.


Asunto(s)
Hiperalgesia/inducido químicamente , Morfina/administración & dosificación , Receptores de Superficie Celular/genética , Animales , Conducta Animal/efectos de los fármacos , Mapeo Cromosómico , Bases de Datos Factuales , Tolerancia a Medicamentos , Genoma , Haplotipos , Heterocigoto , Hiperalgesia/genética , Hiperalgesia/patología , Inyecciones Subcutáneas , Ratones , Ratones Endogámicos C57BL , Morfina/efectos adversos , Morfina/farmacología , Receptores de Netrina , Proteínas/metabolismo , ARN/metabolismo , Receptores de Superficie Celular/metabolismo , Médula Espinal/efectos de los fármacos , Médula Espinal/metabolismo
6.
Mol Pain ; 10: 59, 2014 Sep 12.
Artículo en Inglés | MEDLINE | ID: mdl-25217253

RESUMEN

BACKGROUND: The long term use of opioids for the treatment of pain leads to a group of maladaptations which includes opioid-induced hyperalgesia (OIH). OIH typically resolves within few days after cessation of morphine treatment in mice but is prolonged for weeks if histone deacetylase (HDAC) activity is inhibited during opioid treatment. The present work seeks to identify gene targets supporting the epigenetic effects responsible for OIH prolongation. RESULTS: Mice were treated with morphine according to an ascending dose protocol. Some mice also received the selective HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) additionally. Chronic morphine treatment with simultaneous HDAC inhibition enhanced OIH, and several spinal cord genes were up-regulated. The expression of Bdnf (Brain-derived neurotrophic factor) and Pdyn (Prodynorphin) were most closely related to the observed behavioral changes. ChIP (Chromatin immuoprecipation) assays demonstrated that promoter regions of Pdyn and Bdnf were strongly associated with aceH3K9 (Acetylated histone H3 Lysine9) after morphine and SAHA treatment. Furthermore, morphine treatment caused an increase in spinal BDNF and dynorphin levels, and these levels were further increased in SAHA treated mice. The selective TrkB (tropomyosin-receptor-kinase) antagonist ANA-12 reduced OIH when given one or seven days after cessation of morphine. Treatment with the selective kappa opioid receptor antagonist nor-BNI also reduced established OIH. The co-administration of either receptor antagonist agent daily with morphine resulted in attenuation of hyperalgesia present one day after cessation of treatment. Additionally, repeated morphine exposure induced a rise in BDNF expression that was associated with an increased number of BDNF+ cells in the spinal cord dorsal horn, showing strong co-localization with aceH3K9 in neuronal cells. Lastly, spinal application of low dose BDNF or Dynorphin A after resolution of OIH produced mechanical hypersensitivity, with no effect in controls. CONCLUSIONS: The present study identified two genes whose expression is regulated by epigenetic mechanisms during morphine exposure. Treatments aimed at preventing the acetylation of histones or blocking BDNF and dynorphin signaling may reduce OIH and improve long-term pain using opioids.


Asunto(s)
Analgésicos Opioides/toxicidad , Epigénesis Genética/efectos de los fármacos , Regulación de la Expresión Génica/genética , Hiperalgesia/inducido químicamente , Hiperalgesia/patología , Morfina/toxicidad , Médula Espinal/metabolismo , Animales , Antineoplásicos/administración & dosificación , Azepinas/administración & dosificación , Benzamidas/administración & dosificación , Factor Neurotrófico Derivado del Encéfalo/administración & dosificación , Factor Neurotrófico Derivado del Encéfalo/genética , Modelos Animales de Enfermedad , Dinorfinas/administración & dosificación , Dinorfinas/genética , Regulación de la Expresión Génica/efectos de los fármacos , Ácidos Hidroxámicos/administración & dosificación , Masculino , Ratones , Ratones Endogámicos C57BL , Naltrexona/administración & dosificación , Naltrexona/análogos & derivados , Antagonistas de Narcóticos/administración & dosificación , Dimensión del Dolor/efectos de los fármacos , Médula Espinal/efectos de los fármacos , Vorinostat
7.
Anesth Analg ; 118(6): 1336-44, 2014 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-24755847

RESUMEN

BACKGROUND: Acute pain after surgery remains moderate to severe for 20% to 30% of patients despite advancements in the use of opioids, adjuvant drugs, and regional anesthesia. Depending on the type of surgery, 10% to 50% of patients experience persistent pain postoperatively, and there are no established methods for its prevention. Curcumin (diferuloylmethane) is one of the phenolic constituents of turmeric that has been used in Eastern traditional medicine as an antiseptic, antioxidant, anti-inflammatory, and analgesic agent. It may be effective for treating postoperative pain. METHODS: We used the hindpaw incision model with C57BL/6 mice. Sensitization to mechanical and thermal stimuli as well as effects on edema and temperature were measured up to 7 days after surgery. Spontaneous pain after incision was assessed by using conditioned place preference (CPP), and alterations in gait function were assessed using multiparameter digital gait analysis. RESULTS: Curcumin (50 mg/kg) significantly reduced the intensity of mechanical and heat sensitization after hindpaw incision in mice. No effects of curcumin on baseline nociceptive thresholds were observed. Curcumin also reduced hindpaw swelling after incision, suggesting an anti-inflammatory effect. In addition, perioperative curcumin treatment attenuated hyperalgesic priming due to incision when mice were subsequently challenged with hindpaw prostaglandin E2 application. Furthermore, while vehicle-treated mice had evidence of spontaneous pain 48 hours after incision in the CPP paradigm, no evidence of ongoing pain was observed in the mice treated with curcumin. Likewise, hindpaw incision caused changes in several gait-related indices, but most of these were normalized in the curcumin-treated animals. The peri-incisional levels of several pronociceptive immune mediators including interleukin (IL)-1ß, IL-6, tumor necrosis factor α, and macrophage inflammatory protein-1α were either not reduced or were even augmented 1 and 3 days after incision in curcumin-treated mice. The anti-inflammatory cytokine IL-10 was unchanged, while transforming growth factor-ß levels were enhanced under the same conditions. CONCLUSIONS: Our studies suggest that curcumin treatment is effective in alleviating incision-induced inflammation, nociceptive sensitization, spontaneous pain, and functional gait abnormalities. Augmented transforming growth factor-ß production provides one possible mechanism. These preclinical findings demonstrate curcumin's potential as a preventative strategy in postoperative pain treatment.


Asunto(s)
Dolor Agudo/tratamiento farmacológico , Antiinflamatorios no Esteroideos/farmacología , Curcumina/farmacología , Dolor Postoperatorio/tratamiento farmacológico , Recuperación de la Función/efectos de los fármacos , Animales , Fenómenos Biomecánicos , Temperatura Corporal/efectos de los fármacos , Condicionamiento Operante/efectos de los fármacos , Citocinas/biosíntesis , Edema/patología , Edema/prevención & control , Traumatismos de los Pies/complicaciones , Traumatismos de los Pies/tratamiento farmacológico , Marcha/efectos de los fármacos , Miembro Posterior/lesiones , Masculino , Ratones , Ratones Endogámicos C57BL , Dimensión del Dolor/efectos de los fármacos , Resultado del Tratamiento
8.
J Spinal Disord Tech ; 27(3): E104-9, 2014 May.
Artículo en Inglés | MEDLINE | ID: mdl-23563349

RESUMEN

STUDY DESIGN: The preliminary results from a new anterior-posterior surgical approach are reported. OBJECTIVE: To report a novel surgical approach, which was successfully applied to treat 8 cervical facet dislocation patients. SUMMARY OF BACKGROUND DATA: The combined anterior-posterior surgical procedure is used as a common approach in the treatment of cervical facet dislocations. However, some problems may arise during the application of this approach, and as a result, surgeons must change the initial surgical plan to anterior-posterior-anterior approach. METHODS: Between December 2011 and June 2012, 8 patients had facet dislocations were surgically treated by the new anterior-posterior approach. After anterior discectomy, a peek frame cage containing autologous iliac bone particles or tricalcium phosphate bone substitute was inserted in the interspace and fixed with a peek composite buttress plate screwed into the inferior vertebral body. Then, the anterior wound was closed and the patient was turned prone. Through a posterior midline approach, the posterior elements were exposed and the reduction was gradually achieved by posteriorly translating the superior segment and progressively positioning the patient's neck into extension. Then lateral mass or pedicle screws and titanium rods were placed in a favorable and satisfactory position, which was demonstrated by the intraoperative plain radiographs. A posterolateral fusion was performed and the posterior wound was closed. RESULTS: With the use of this new approach, all the patients had obtained successful reduction and satisfactory anatomic sagittal alignment. No instances of neurological deterioration and instrument failure occurred, no complications were owing to the use of this technique, and 4 patients existed neurological functional recovery at the most recent follow-up visit. CONCLUSIONS: This reported surgical approach is an efficient and safe way for the treatment of traumatic cervical facet dislocations.


Asunto(s)
Vértebras Cervicales/cirugía , Luxaciones Articulares/cirugía , Procedimientos Ortopédicos/métodos , Articulación Cigapofisaria/cirugía , Adulto , Vértebras Cervicales/diagnóstico por imagen , Femenino , Humanos , Ilion/cirugía , Imagenología Tridimensional , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Cuidados Preoperatorios , Tomografía Computarizada por Rayos X
9.
Anesthesiology ; 119(5): 1198-208, 2013 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-23756451

RESUMEN

BACKGROUND: The regulation of gene expression in nociceptive pathways contributes to the induction and maintenance of pain sensitization. Histone acetylation is a key epigenetic mechanism controlling chromatin structure and gene expression. Chemokine CC motif receptor 2 (CXCR2) is a proinflammatory receptor implicated in neuropathic and inflammatory pain and is known to be regulated by histone acetylation in some settings. The authors sought to investigate the role of histone acetylation on spinal CXCR2 signaling after incision. METHODS: Groups of 5-8 mice underwent hind paw incision. Suberoylanilide hydroxamic acid and anacardic acid were used to inhibit histone deacetylase and histone acetyltransferase, respectively. Behavioral measures of thermal and mechanical sensitization as well as hyperalgesic priming were used. Both message RNA quantification and chromatin immunoprecipitation analysis were used to study the regulation of CXCR2 and ligand expression. Finally, the selective CXCR2 antagonist SB225002 was administered intrathecally to reveal the function of spinal CXCR2 receptors after hind paw incision. RESULTS: Suberoylanilide hydroxamic acid significantly exacerbated mechanical sensitization after incision. Conversely, anacardic acid reduced incisional sensitization and also attenuated incision-induced hyperalgesic priming. Overall, acetylated histone H3 at lysine 9 was increased in spinal cord tissues after incision, and enhanced association of acetylated histone H3 at lysine 9 with the promoter regions of CXCR2 and keratinocyte-derived chemokine (CXCL1) was observed as well. Blocking CXCR2 reversed mechanical hypersensitivity after hind paw incision. CONCLUSIONS: Histone modification is an important epigenetic mechanism regulating incision-induced nociceptive sensitization. The spinal CXCR2 signaling pathway is one epigenetically regulated pathway controlling early and latent sensitization after incision.


Asunto(s)
Epigénesis Genética/fisiología , Hiperalgesia/genética , Periodo Intraoperatorio , Nocicepción/fisiología , Receptores de Interleucina-8B/genética , Receptores de Interleucina-8B/fisiología , Transducción de Señal/genética , Transducción de Señal/fisiología , Médula Espinal/fisiopatología , Ácidos Anacárdicos/administración & dosificación , Ácidos Anacárdicos/farmacología , Animales , Antiinflamatorios no Esteroideos/farmacología , Western Blotting , Inmunoprecipitación de Cromatina , Dinoprostona/administración & dosificación , Dinoprostona/farmacología , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/farmacología , Epigénesis Genética/efectos de los fármacos , Histona Acetiltransferasas/antagonistas & inhibidores , Inhibidores de Histona Desacetilasas/farmacología , Ácidos Hidroxámicos/farmacología , Hiperalgesia/etiología , Inmunohistoquímica , Masculino , Ratones , Ratones Endogámicos C57BL , Dimensión del Dolor/efectos de los fármacos , Compuestos de Fenilurea/farmacología , Estimulación Física , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptores de Interleucina-8B/antagonistas & inhibidores , Transducción de Señal/efectos de los fármacos , Médula Espinal/efectos de los fármacos , Vorinostat
10.
Anesthesiology ; 116(4): 882-95, 2012 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-22343473

RESUMEN

BACKGROUND: Patients with complex regional pain syndrome have increased tryptase in the skin of the affected extremity indicating mast cell (MC) accumulation and degranulation, processes known to be mediated by substance P (SP). The dysregulation of SP release from primary afferent neurons is characteristic of complex regional pain syndrome. The authors hypothesized that SP acting through the neurokinin-1 receptor results in mast cell accumulation, degranulation, and nociceptive sensitization in a rat model of complex regional pain syndrome. METHODS: Groups of 6-10 rats underwent tibia fracture and hind limb casting for 4 weeks, and the hind paw skin was harvested for histologic and immunohistochemical analysis. The effects of a selective neurokinin-1 receptor antagonist (LY303870) and of direct SP intraplantar injection were measured. Dermal MC degranulation induced by sciatic nerve stimulation and the effects of LY303870 on this process were investigated. Finally, the antinociceptive effects of acute and chronic treatment with a MC degranulator (48/80) were tested. RESULTS: The authors observed that fracture caused MC accumulation, activation, and degranulation, which were inhibited by LY303870; the percentage of MCs in close proximity to peptidergic nerve fibers increased after fracture; electrical stimulation caused MC activation and degranulation, which was blocked by LY303870; intraplantar SP-induced MC degranulation and acute administration of 48/80 caused MC degranulation and enhanced postfracture nociception, but MC-depleted animals showed less sensitization. CONCLUSIONS: These results indicate that facilitated peptidergic neuron-MC signaling after fracture can cause MC accumulation, activation, and degranulation in the injured limb, resulting in nociceptive sensitization.


Asunto(s)
Síndromes de Dolor Regional Complejo/metabolismo , Modelos Animales de Enfermedad , Mastocitos/metabolismo , Nocicepción/fisiología , Sustancia P/fisiología , Fracturas de la Tibia/metabolismo , Animales , Síndromes de Dolor Regional Complejo/patología , Indoles/farmacología , Masculino , Mastocitos/efectos de los fármacos , Antagonistas del Receptor de Neuroquinina-1 , Dimensión del Dolor/efectos de los fármacos , Dimensión del Dolor/métodos , Piperidinas/farmacología , Ratas , Ratas Sprague-Dawley , Receptores de Neuroquinina-1/metabolismo
11.
Anesthesiology ; 117(3): 626-38, 2012 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-22846677

RESUMEN

BACKGROUND: After incision keratinocytes in the epidermis become activated to produce a range of pain-related mediators. microRNA 203 (miR-203) is known to be involved in keratinocyte growth, differentiation, and skin inflammation. We hypothesized that one or more of these mediators might be under the control of miR-203. METHODS: The expression of miR-203 and its target gene, phospholipase A2 activating protein (PLAA), were examined after hind paw incision in mice. We investigated the local effect of intraplantar PLAA peptide injection in normal mice and the effects of a selective secretory phospholipase A2 inhibitor (HK064) on PLAA or incision-induced mechanical allodynia. Last, we investigated the role of substance P signaling in regulating miR-203 and PLAA expression in vitro and in vivo. RESULTS: Levels of miR-203 were strongly down-regulated in keratinocytes after incision. Informatics-based approaches identified PLAA as a likely candidate for regulation by miR-203. PLAA caused mechanical allodynia and conditioned place aversion but not thermal sensitization. HK064 reduced mechanical allodynia after incision and after intraplantar injection of PLAA. Using preprotachykinin gene knockout mice or with neurokinin-1 selective antagonist LY303870 treatment, we observed that substance P-mediated signaling was also required for miR-203 and PLAA regulation after incision. Finally, using the rat epidermal keratinocyte cell line, we observed that a miR-203 mimic molecule could block the substance P-induced increase in PLAA expression observed under control conditions. CONCLUSIONS: miR-203 may regulate expression of the novel nociceptive mediator PLAA after incision. Furthermore, the regulation of miR-203 and PLAA levels is reliant upon intact substance P signaling.


Asunto(s)
MicroARNs/fisiología , Dolor/fisiopatología , Proteínas/fisiología , Animales , Condicionamiento Psicológico , Masculino , Ratones , Ratones Endogámicos C57BL , Precursores de Proteínas/fisiología , Receptores de Neuroquinina-1/fisiología , Transducción de Señal/fisiología , Sustancia P/fisiología , Taquicininas/fisiología
12.
J Neuroinflammation ; 8: 80, 2011 Jul 07.
Artículo en Inglés | MEDLINE | ID: mdl-21736743

RESUMEN

BACKGROUND: In our previous study, we demonstrated that local injection of complement C5a and C3a produce mechanical and heat hyperalgesia, and that C5a and C3a activate and sensitize cutaneous nociceptors in normal skin, suggesting a contribution of complement fragments to acute pain. Other studies also have shown that the complement system can be activated by surgical incision, and the systemic blockade of C5a receptor (C5aR) reduces incision-induced pain and inflammation. In this study, we further examined the possible contribution of wound area C5a to incisional pain. METHODS: Using of a hind paw incisional model, the effects of a selective C5aR antagonist, PMX53, on nociceptive behaviors were measured after incision in vivo. mRNA levels of C5 and C5aR in skin, dorsal root ganglia (DRG) and spinal cord, and C5a protein levels in the skin were quantified after incision. The responses of nociceptors to C5a were also evaluated using the in vitro skin-nerve preparation. RESULTS: Local administration of PMX53 suppressed heat hyperalgesia and mechanical allodynia induced by C5a injection or after hind paw incision in vivo. mRNA levels of C5 and C5aR in the skin, but not DRG and spinal cord, were dramatically increased after incision. C5a protein in the skin was also increased after incision. In vitro C5a did not increase the prevalence of fibers with ongoing activity in afferents from incised versus control, unincised skin. C5a sensitized C-fiber afferent responses to heat; however, this was less evident in afferents adjacent to the incision. PMX53 blocked sensitization of C-fiber afferents to heat by C5a but did not by itself influence ongoing activity or heat sensitivity in afferents innervating control or incised skin. The magnitude of mechanical responses was also not affected by C5a in any nociceptive fibers innervating incised or unincised skin. CONCLUSIONS: This study demonstrates that high locally generated C5a levels are present in wounds for at least 72 hours after incision. In skin, C5a contributes to hypersensitivity after incision, but increased responsiveness of cutaneous nociceptors to C5a was not evident in incised skin. Thus, high local concentrations of C5a produced in wounds likely contribute to postoperative pain.


Asunto(s)
Complemento C5a/metabolismo , Nociceptores/fisiología , Dolor Postoperatorio/fisiopatología , Piel/inervación , Animales , Conducta Animal , Complemento C5a/genética , Ganglios Espinales/metabolismo , Hiperalgesia/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Fibras Nerviosas Amielínicas/efectos de los fármacos , Fibras Nerviosas Amielínicas/fisiología , Dimensión del Dolor , Umbral del Dolor , Péptidos Cíclicos/farmacología , Receptor de Anafilatoxina C5a/antagonistas & inhibidores , Receptor de Anafilatoxina C5a/genética , Receptor de Anafilatoxina C5a/metabolismo , Piel/efectos de los fármacos , Médula Espinal/metabolismo
13.
Anesthesiology ; 114(5): 1180-9, 2011 May.
Artículo en Inglés | MEDLINE | ID: mdl-21368652

RESUMEN

BACKGROUND: Opioid-induced hyperalgesia (OIH) and tolerance are challenging maladaptations associated with opioids in managing pain. Recent genetic studies and the existing literature suggest the 5-hydroxytryptamine type 3 (5-HT3) receptor participates in these phenomena. The location of the relevant receptor populations and the interactions between the 5-HT3 system and other systems controlling OIH and tolerance have not been explored, however. We hypothesized that 5-HT3 receptors modulate OIH and tolerance, and that this modulation involves the control of expression of multiple neurotransmitter and receptor systems. METHODS: C57BL/6 mice were exposed to a standardized 4-day morphine administration protocol. The 5-HT3 antagonist ondansetron was administered either during or after the conclusion of morphine administration. Mechanical testing was used to quantify OIH, and thermal tail-flick responses were used to measure morphine tolerance. In other experiments spinal cord and dorsal root ganglion tissues were harvested for analysis of messenger RNA concentrations by real-time polymerase chain reaction or immunochemistry analysis. RESULTS: The results showed that (1) systemic or intrathecal injection of ondansetron significantly prevented and reversed OIH, but not local intraplantar injection; (2) systemic or intrathecal injection of ondansetron prevented and reversed tolerance; and (3) ondansetron blocked morphine-induced increases of multiple genes relevant to OIH and tolerance in dorsal root ganglion and spinal cord. CONCLUSIONS: Morphine acts via a 5-HT3-dependent mechanism to support multiple maladaptations to the chronic administration of morphine. Furthermore, the use of 5-HT3 receptor antagonists may provide a new avenue to prevent or reverse OIH and tolerance associated with chronic opioid use.


Asunto(s)
Analgésicos Opioides/efectos adversos , Hiperalgesia/inducido químicamente , Hiperalgesia/metabolismo , Morfina/efectos adversos , Ondansetrón/administración & dosificación , Receptores de Serotonina 5-HT3/metabolismo , Antagonistas de la Serotonina/administración & dosificación , Animales , Tolerancia a Medicamentos , Ganglios Espinales/efectos de los fármacos , Ganglios Espinales/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa
14.
Anesthesiology ; 113(4): 945-56, 2010 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-20823759

RESUMEN

BACKGROUND: Surgical injury induces production and release of inflammatory mediators in the vicinity of the wound. They in turn trigger nociceptive signaling to produce hyperalgesia and pain. Interleukin-1ß plays a crucial role in this process. The mechanism regulating production of this cytokine after incision is, however, unknown. Caspase-1 is a key enzyme that cleaves prointerleukin-1ß to its active form. We hypothesized that caspase-1 is a crucial regulator of incisional interleukin-1ß levels, nociceptive sensitization, and inflammation. METHODS: These studies employed a mouse hind paw incisional model. Caspase-1 was blocked using the selective inhibitors Ac-YVAD-CMK and VRTXSD727. Nociceptive sensitization, edema, and hind paw warmth were followed in intact animals whereas caspase-1 activity, cytokine, and prostaglandin E2 levels were assessed in homogenized skin. Confocal microscopy was used to detect the expression of caspase-1 near the wounds. RESULTS: Analysis of enzyme activity demonstrated that caspase-1 activity was significantly increased in periincisional skin. Pretreatment with Ac-YVAD-CMK significantly reduced mechanical allodynia and thermal hyperalgesia. Repeated administration of this inhibitor produced robust analgesia, especially to mechanical stimulation. Administration of VRTXSD727 provided qualitatively similar results. Caspase-1 inhibition also reduced edema and the normally observed increase in paw warmth around the wound site. Correspondingly, caspase-1 inhibition significantly reduced interleukin-1ß as well as macrophage-inflammatory protein 1α, granulocyte colony-stimulating factor, and prostaglandin E2 levels near the wound. The expression of caspase-1 was primarily observed in keratinocytes in the epidermal layer and in neutrophils deeper in the wounds. CONCLUSIONS: The current study demonstrates that the inhibition of caspase-1 reduces postsurgical sensitization and inflammation, likely through a caspase-1/interleukin-1ß-dependent mechanism.


Asunto(s)
Caspasa 1/fisiología , Inflamación/patología , Procedimientos Quirúrgicos Operativos/efectos adversos , Animales , Biomarcadores , Temperatura Corporal/efectos de los fármacos , Inhibidores de Caspasas , Quimiocina CCL3/metabolismo , Dinoprostona/metabolismo , Edema/patología , Factor Estimulante de Colonias de Granulocitos/líquido cefalorraquídeo , Miembro Posterior/patología , Calor , Hiperalgesia/fisiopatología , Inmunohistoquímica , Inflamación/metabolismo , Interleucina-1beta/metabolismo , Masculino , Ratones , Ratones Endogámicos BALB C , Dolor/psicología , Dimensión del Dolor , Umbral del Dolor/fisiología , Piel/metabolismo
15.
Anesth Analg ; 111(6): 1525-33, 2010 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-20889942

RESUMEN

BACKGROUND: Wound healing is a multistep, complex process that involves the coordinated action of multiple cell types. Conflicting results have been obtained when conventional methods have been used to study wound biology. Therefore, we analyzed the wound response in a mouse genetic model. METHODS: We analyzed inflammatory mediators produced within incisional wounds induced in 16 inbred mouse strains. Computational haplotype-based genetic analysis of inter-strain differences in the level of production of 2 chemokines in wounds was performed. An in vitro experimental analysis system was developed to investigate whether interleukin (IL)-1 could affect chemokine production by 2 different types of cells that are present within wounds. RESULTS: The level of 2 chemokines, keratinocyte-derived chemokine (KC) and macrophage inflammatory protein 1α, exhibited very large (75- and 463-fold, respectively) interstrain differences within wound tissue across this inbred strain panel. Genetic variation within Nalp1, an inflammasome component that regulates IL-1 production, correlated with the interstrain differences in KC and macrophage inhibitory protein 1α production. Consistent with the genetic correlation, IL-1ß was shown to stimulate KC production by murine keratinocyte and fibroblast cell lines in vitro. CONCLUSIONS: Genetic variation within Nalp1 could contribute to interstrain differences in wound chemokine production by altering the amount of IL-1 produced.


Asunto(s)
Quimiocina CCL3/metabolismo , Quimiocinas/metabolismo , Procedimientos Quirúrgicos Dermatologicos , Mediadores de Inflamación/metabolismo , Interleucina-1/metabolismo , Cicatrización de Heridas , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Proteínas Reguladoras de la Apoptosis/genética , Proteínas Reguladoras de la Apoptosis/metabolismo , Células Cultivadas , Quimiocina CCL3/genética , Quimiocinas/genética , Genómica , Haplotipos , Inmunohistoquímica , Interleucina-1/genética , Interleucina-1alfa/metabolismo , Interleucina-1beta/metabolismo , Queratinocitos/inmunología , Macrófagos Peritoneales/inmunología , Ratones , Ratones Endogámicos , Fenotipo , Piel/inmunología , Especificidad de la Especie , Factores de Tiempo , Cicatrización de Heridas/genética
16.
Anesth Analg ; 111(6): 1534-42, 2010 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-20889944

RESUMEN

BACKGROUND: In the accompanying paper, we demonstrate that genetic variation within Nalp1 could contribute to interstrain differences in wound chemokine production through altering the amount of interleukin (IL)-1 produced. We further investigate the role of IL-1 in incisional wound biology and its effect on wound chemokine production in vivo and whether this mechanism could be active in human subjects. METHODS: A well-characterized murine model of incisional wounding was used to assess the in vivo role of IL-1 in wound biology. The amount of 7 different cytokines/chemokines produced within an experimentally induced skin incision on a mouse paw and the nociceptive response was analyzed in mice treated with an IL-1 inhibitor. We also investigated whether human IL-1ß or IL-1α stimulated the production of chemokines by primary human keratinocytes in vitro, and whether there was a correlation between IL-1ß and chemokine levels in 2 experimental human wound paradigms. RESULTS: Administration of an IL-1 receptor antagonist to mice decreased the nociceptive response to an incisional wound, and reduced the production of multiple inflammatory mediators, including keratinocyte-derived chemokine (KC) and macrophage inhibitory protein (MIP)-1α, within the wounds. IL-1α and IL-1ß stimulated IL-8 and GRO-α (human homologues of murine keratinocyte-derived chemokine) production by primary human keratinocytes in vitro. IL-1ß levels were highly correlated with IL-8 in human surgical wounds, and at cutaneous sites of human ultraviolet B-induced sunburn injury. CONCLUSIONS: IL-1 plays a major role in regulating inflammatory mediator production in wounds through a novel mechanism; by stimulating the production of multiple cytokines and chemokines, it impacts clinically important aspects of wound biology. These data suggest that administration of an IL-1 receptor antagonist within the perioperative period could decrease postsurgical wound pain.


Asunto(s)
Quimiocinas/metabolismo , Procedimientos Quirúrgicos Dermatologicos , Mediadores de Inflamación/metabolismo , Interleucina-1/metabolismo , Queratinocitos/inmunología , Cicatrización de Heridas , Analgésicos/farmacología , Animales , Antiinflamatorios/farmacología , Células Cultivadas , Cesárea , Quimiocina CCL3/metabolismo , Quimiocina CXCL1/metabolismo , Modelos Animales de Enfermedad , Femenino , Humanos , Proteína Antagonista del Receptor de Interleucina 1/farmacología , Interleucina-1alfa/metabolismo , Interleucina-1beta/metabolismo , Interleucina-8/metabolismo , Queratinocitos/efectos de los fármacos , Queratinocitos/efectos de la radiación , Masculino , Ratones , Ratones Endogámicos C57BL , Dolor Postoperatorio/inmunología , Dolor Postoperatorio/prevención & control , Embarazo , Ensayos Clínicos Controlados Aleatorios como Asunto , Piel/efectos de los fármacos , Piel/inmunología , Piel/efectos de la radiación , Quemadura Solar/inmunología , Factores de Tiempo , Investigación Biomédica Traslacional , Cicatrización de Heridas/efectos de los fármacos
17.
Sci Rep ; 9(1): 19500, 2019 12 20.
Artículo en Inglés | MEDLINE | ID: mdl-31863005

RESUMEN

High rates of acute and chronic pain are associated with traumatic brain injury (TBI), but mechanisms responsible for the association remain elusive. Recent data suggest dysregulated descending pain modulation circuitry could be involved. Based on these and other observations, we hypothesized that serotonin (5-HT)-dependent activation of spinal CXC Motif Chemokine Receptor 2 (CXCR2) may support TBI-related nociceptive sensitization in a mouse model of mild TBI (mTBI). We observed that systemic 5-HT depletion with p-chlorophenylalanine attenuated mechanical hypersensitivity seen after mTBI. Likewise, selective spinal 5-HT fiber depletion with 5,7-dihydroxytryptamine (5,7-DHT) reduced hypersensitivity after mTBI. Consistent with a role for spinal 5-HT3 serotonin receptors, intrathecal ondansetron administration after TBI dose-dependently attenuated nociceptive sensitization. Also, selective CXCR2 antagonist SCH527123 treatment attenuated mechanical hypersensitivity after mTBI. Furthermore, spinal CXCL1 and CXCL2 mRNA and protein levels were increased after mTBI as were GFAP and IBA-1 markers. Spinal 5,7-DHT application reduced both chemokine expression and glial activation. Our results suggest dual pathways for nociceptive sensitization after mTBI, direct 5-HT effect through 5-HT3 receptors and indirectly through upregulation of chemokine signaling. Designing novel clinical interventions against either the 5-HT3 mediated component or chemokine pathway may be beneficial in treating pain frequently seen in patients after mTBI.


Asunto(s)
Lesiones Traumáticas del Encéfalo/metabolismo , Receptores de Serotonina 5-HT1/metabolismo , 5,7-Dihidroxitriptamina/farmacología , Animales , Benzamidas/farmacología , Quimiocina CXCL1/genética , Quimiocina CXCL1/metabolismo , Quimiocina CXCL2/genética , Quimiocina CXCL2/metabolismo , Ciclobutanos/farmacología , Modelos Animales de Enfermedad , Ensayo de Inmunoadsorción Enzimática , Fenclonina/farmacología , Inmunohistoquímica , Masculino , Ratones , Ondansetrón/uso terapéutico , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptores de Interleucina-8B/antagonistas & inhibidores , Receptores de Interleucina-8B/metabolismo , Receptores de Serotonina 5-HT3/metabolismo
18.
Neuromolecular Med ; 21(2): 170-181, 2019 06.
Artículo en Inglés | MEDLINE | ID: mdl-30900118

RESUMEN

Mild traumatic brain injury (mTBI) can result in permanent impairment in memory and learning and may be a precursor to other neurological sequelae. Clinical treatments to ameliorate the effects of mTBI are lacking. Inhibition of microRNA-181a (miR-181a) is protective in several models of cerebral injury, but its role in mTBI has not been investigated. In the present study, miR-181a-5p antagomir was injected intracerebroventricularly 24 h prior to closed-skull cortical impact in young adult male mice. Paw withdrawal, open field, zero maze, Y maze, object location and novel object recognition tests were performed to assess neurocognitive dysfunction. Brains were assessed immunohistologically for the neuronal marker NeuN, the perineuronal net marker wisteria floribunda lectin (WFA), cFos, and the interneuron marker parvalbumin. Protein quantification was performed with immunoblots for synaptophysin and postsynaptic density 95 (PSD95). Fluorescent in situ hybridization was utilized to localize hippocampal miR-181a expression. MiR-181a antagomir treatment reduced neuronal miR-181a expression after mTBI, restored deficits in novel object recognition and increased hippocampal parvalbumin expression in the dentate gyrus. These changes were associated with decreased dentate gyrus hyperactivity indicated by a relative reduction in PSD95 and cFos expression. These results suggest that miR-181a inhibition may be a therapeutic approach to reduce hippocampal excitotoxicity and prevent cognitive dysfunction following mTBI.


Asunto(s)
Antagomirs/uso terapéutico , Lesiones Traumáticas del Encéfalo/terapia , Conducta Exploratoria/efectos de los fármacos , Traumatismos Cerrados de la Cabeza/terapia , MicroARNs/antagonistas & inhibidores , Parvalbúminas/biosíntesis , Reconocimiento en Psicología/efectos de los fármacos , Animales , Antagomirs/administración & dosificación , Antagomirs/farmacología , Lesiones Traumáticas del Encéfalo/genética , Lesiones Traumáticas del Encéfalo/metabolismo , Corteza Cerebral/química , Corteza Cerebral/lesiones , Corteza Cerebral/patología , Simulación por Computador , Traumatismos Cerrados de la Cabeza/genética , Traumatismos Cerrados de la Cabeza/metabolismo , Hipocampo/química , Hipocampo/lesiones , Hipocampo/patología , Hiperalgesia/etiología , Hiperalgesia/genética , Hiperalgesia/prevención & control , Masculino , Aprendizaje por Laberinto , Trastornos de la Memoria/etiología , Trastornos de la Memoria/genética , Trastornos de la Memoria/prevención & control , Ratones , Ratones Endogámicos C57BL , MicroARNs/biosíntesis , MicroARNs/genética , Prueba de Campo Abierto , Parvalbúminas/genética , Premedicación , Distribución Aleatoria , Método Simple Ciego , Sinapsis/química
19.
Mol Pain ; 4: 7, 2008 Feb 22.
Artículo en Inglés | MEDLINE | ID: mdl-18294378

RESUMEN

BACKGROUND: The chronic use of opioids prior to surgery leads to lowered pain thresholds and exaggerated pain levels after these procedures. Several mechanisms have been proposed to explain this heightened sensitivity commonly termed opioid-induced hyperalgesia (OIH). Most of these proposed mechanisms involve plastic events in the central or peripheral nervous systems. Alterations in the abundance of peripheral mediators of nociception have not previously been explored. RESULTS: In these experiments mice were treated with saline (control) or ascending daily doses of morphine to generate a state of OIH followed by hind paw incision. In other experiments morphine treatment was initiated at the time of incision. Both mechanical allodynia and peri-incisional skin cytokine levels were measured. Myeloperoxidase (MPO) assays were used to determine neutrophil activity near the wounds. The cytokine production inhibitor pentoxifylline was used to determine the functional significance of the excess cytokines in previously morphine treated animals. Mice treated chronically treated with morphine prior to incision were found to have enhanced skin levels of IL-1beta, IL-6, G-CSF, KC and TNFalpha after incision at one or more time points compared to saline pretreated controls. The time courses of individual cytokines followed different patterns. There was no discernable effect of chronic morphine treatment on wound area neutrophil infiltration. Pentoxifylline reduced cytokine levels and reversed the excess mechanical sensitization caused by chronic morphine administration prior to incision. Morphine treatment initiated at the time of incision did not lead to a generalized enhancement of cytokine production or nociceptive sensitization in excess of the levels observed after incision alone. CONCLUSION: The enhanced level of nociceptive sensitization seen after incision in animals chronically exposed to morphine is associated with elevated levels of several cytokines previously reported to be relevant to this incisional pain model. The cytokines may be functional in supporting nociceptive sensitization because pentoxifylline reverses both peri-incisional skin cytokine levels and OIH. Opioid administration beginning at the time of incision does not seem to have the same cytokine enhancing effect. Approaches to postoperative pain control involving a reduction of cytokines may be an effective way to control excessive pain in patients chronically using opioids prior to surgical procedures.


Asunto(s)
Citocinas/biosíntesis , Miembro Posterior/patología , Morfina/administración & dosificación , Morfina/farmacología , Nociceptores/metabolismo , Umbral del Dolor/efectos de los fármacos , Animales , Miembro Posterior/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Dimensión del Dolor , Pentoxifilina/farmacología , Peroxidasa/metabolismo
20.
Neurochirurgie ; 64(3): 166-170, 2018 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-29735379

RESUMEN

OBJECTIVE: Postoperative hematoma is a rare and dangerous complication of cervical spine surgery. The aim of this study was to investigate the incidence and related factors of postoperative hematoma, and to report on 15 cases at our institution over a 6-year period. METHODS: Fifteen cases of postoperative hematoma were retrospectively identified. We investigated their neurological outcomes, characteristics, and surgical data, and identified risk factors associated with postoperative (PO) hematoma. Patients with hematoma were compared to those with no hematoma, in order to identify risk factors. RESULTS: Retropharyngeal hematomas developed in seven cases and epidural hematomas in eight. The total incidence of postoperative hematoma was 1.2%: 0.5% retropharyngeal hematomas and 0.6% spinal epidural hematomas. At time of onset, the severity of paralysis was assessed as grade B in one case, grade C in six cases, and grade D in eight cases. Risk factors for PO hematoma were: (1) presence of ossification of the posterior longitudinal ligament (OPLL) (P<0.001); (2) longer operative duration (P=0.048); (3) greater number of surgical levels (P=0.02); and (4) higher body mass index (BMI; P=0.035). There was no significant difference in modified Japan Orthopedic Association scores between the hematoma group and non-hematoma group (P>0.05). CONCLUSION: Precise preoperative preparation and systematic evaluation are central to successful management of PO hematoma after anterior cervical surgery. Risk factors for PO hematoma include multilevel decompression, OPLL, higher BMI, and longer operation time.


Asunto(s)
Vértebras Cervicales/cirugía , Hematoma Espinal Epidural/epidemiología , Hematoma Espinal Epidural/cirugía , Adulto , Anciano , Descompresión Quirúrgica/métodos , Femenino , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Procedimientos Neuroquirúrgicos/efectos adversos , Parálisis/etiología , Estudios Retrospectivos , Factores de Riesgo , Factores de Tiempo , Resultado del Tratamiento
SELECCIÓN DE REFERENCIAS
Detalles de la búsqueda