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1.
Pain ; 115(1-2): 128-41, 2005 May.
Artículo en Inglés | MEDLINE | ID: mdl-15836976

RESUMEN

Bone cancer pain can be difficult to control, as it appears to be driven simultaneously by inflammatory, neuropathic and tumorigenic mechanisms. As nerve growth factor (NGF) has been shown to modulate inflammatory and neuropathic pain states, we focused on a novel NGF sequestering antibody and demonstrated that two administrations of this therapy in a mouse model of bone cancer pain produces a profound reduction in both ongoing and movement-evoked bone cancer pain-related behaviors that was greater than that achieved with acute administration of 10 or 30 mg/kg of morphine. This therapy also reduced several neurochemical changes associated with peripheral and central sensitization in the dorsal root ganglion and spinal cord, whereas the therapy did not influence disease progression or markers of sensory or sympathetic innervation in the skin or bone. Mechanistically, the great majority of sensory fibers that innervate the bone are CGRP/TrkA expressing fibers, and if the sensitization and activation of these fibers is blocked by anti-NGF therapy there would not be another population of nociceptors, such as the non-peptidergic IB4/RET-IR nerve fibers, to take their place in signaling nociceptive events.


Asunto(s)
Anticuerpos Monoclonales/administración & dosificación , Neoplasias Femorales/complicaciones , Neoplasias Femorales/tratamiento farmacológico , Factor de Crecimiento Nervioso/inmunología , Nociceptores/efectos de los fármacos , Dolor/etiología , Dolor/prevención & control , Animales , Biomarcadores/metabolismo , Neoplasias Femorales/diagnóstico , Masculino , Ratones , Ratones Endogámicos C3H , Nociceptores/metabolismo , Dolor/diagnóstico , Nervios Periféricos/efectos de los fármacos , Nervios Periféricos/metabolismo , Sarcoma/complicaciones , Sarcoma/diagnóstico , Sarcoma/tratamiento farmacológico , Médula Espinal/efectos de los fármacos , Médula Espinal/metabolismo , Resultado del Tratamiento , Células Tumorales Cultivadas
2.
Pain ; 119(1-3): 233-246, 2005 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-16298491

RESUMEN

To begin to understand the relationship between disease progression and pain in pancreatic cancer, transgenic mice that develop pancreatic cancer due to the expression of the simian virus 40 large T antigen under control of the rat elastase-1 promoter were examined. In these mice precancerous cellular changes were evident at 6 weeks and these included an increase in: microvascular density, macrophages that express nerve growth factor and the density of sensory and sympathetic fibers that innervate the pancreas, with all of these changes increasing with tumor growth. In somatic tissue such as skin, the above changes would be accompanied by significant pain; however, in mice with pancreatic cancer, changes in pain-related behaviors, such as morphine-reversible severe hunching and vocalization only became evident at 16 weeks of age, by which time the pancreatic cancer was highly advanced. These data suggest that in mice as well as humans, there is a stereotypic set of pathological changes that occur as pancreatic cancer develops, and while weight loss generally tracks disease progression, there is a significant lag between disease progression and behaviors indicative of pancreatic cancer pain. Defining the mechanisms that mask this pain in early and mid-stage disease and drive the pain in late-stage disease may aid in earlier diagnosis, survival, and increased quality of life of patients with pancreatic cancer.


Asunto(s)
Peso Corporal , Neovascularización Patológica/patología , Dolor/fisiopatología , Páncreas/inervación , Páncreas/fisiopatología , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/fisiopatología , Animales , Progresión de la Enfermedad , Activación de Macrófagos/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Dolor/diagnóstico , Dolor/etiología , Páncreas/irrigación sanguínea , Páncreas/patología , Neoplasias Pancreáticas/irrigación sanguínea , Neoplasias Pancreáticas/complicaciones , Lesiones Precancerosas/irrigación sanguínea , Lesiones Precancerosas/patología , Lesiones Precancerosas/fisiopatología , Estadística como Asunto
3.
Exp Neurol ; 203(1): 42-54, 2007 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-17005179

RESUMEN

Paclitaxel-induced peripheral neuropathy (PN) can be a significant problem for patients receiving chemotherapeutic regimens for the treatment of breast, ovarian, and lung cancer as PN can influence the quality of life and survivorship in these patients. To begin to understand the cellular changes that occur within the peripheral and central nervous system as PN develops, we intravenously infused rats with clinically relevant doses of paclitaxel. Ten days later, behavioral changes indicative of PN became evident that included mechanical allodynia, cold hyperalgesia, and deficits in ambulation/coordination. These behaviors were accompanied by increased expression of activating transcription factor 3 (ATF3; a marker of cellular injury) in a population of large>medium>small diameter sensory neurons, a population of satellite cells in the lumbar dorsal root ganglia (DRG) and in myelinating Schwann cells in the sciatic nerve. In addition, there was an increase in the expression of glial fibrillary acidic protein (GFAP) in DRG satellite cells and an increase in the number of CD68 positive activated macrophages within the DRG and peripheral nerve. Within lamina III-IV of the lumbar spinal cord, there was an increase in OX42 positive microglia. These data suggest that intravenous infusion of paclitaxel induces a peripheral neuropathy characterized by injury of neuronal and non-neuronal cells in the peripheral nervous system, macrophage activation in both the DRG and peripheral nerve, and microglial activation within the spinal cord. An understanding of the factors involved in the development and maintenance of PN may lead to mechanism based therapies that prevent/treat PN and thus improve the survival and quality of life of patients receiving chemotherapy.


Asunto(s)
Quimiotaxis de Leucocito/efectos de los fármacos , Macrófagos/efectos de los fármacos , Neuronas Aferentes/efectos de los fármacos , Paclitaxel/toxicidad , Nervios Periféricos/efectos de los fármacos , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Factor de Transcripción Activador 3/efectos de los fármacos , Factor de Transcripción Activador 3/metabolismo , Animales , Antígenos CD/efectos de los fármacos , Antígenos CD/metabolismo , Antígenos de Diferenciación Mielomonocítica/efectos de los fármacos , Antígenos de Diferenciación Mielomonocítica/metabolismo , Antineoplásicos Fitogénicos/toxicidad , Antígeno CD11b , Quimiotaxis de Leucocito/fisiología , Modelos Animales de Enfermedad , Ganglios Espinales/efectos de los fármacos , Ganglios Espinales/metabolismo , Ganglios Espinales/patología , Proteína Ácida Fibrilar de la Glía/efectos de los fármacos , Proteína Ácida Fibrilar de la Glía/metabolismo , Hiperalgesia/inducido químicamente , Hiperalgesia/patología , Hiperalgesia/fisiopatología , Inyecciones Intravenosas , Macrófagos/metabolismo , Masculino , Microglía/efectos de los fármacos , Microglía/metabolismo , Microglía/patología , Neuronas Aferentes/metabolismo , Neuronas Aferentes/patología , Nervios Periféricos/patología , Nervios Periféricos/fisiopatología , Enfermedades del Sistema Nervioso Periférico/patología , Enfermedades del Sistema Nervioso Periférico/fisiopatología , Células del Asta Posterior/efectos de los fármacos , Células del Asta Posterior/metabolismo , Células del Asta Posterior/patología , Ratas , Ratas Sprague-Dawley , Células Satélites Perineuronales/efectos de los fármacos , Células Satélites Perineuronales/metabolismo , Células Satélites Perineuronales/patología , Células de Schwann/efectos de los fármacos , Células de Schwann/metabolismo , Células de Schwann/patología
4.
Gastroenterology ; 131(3): 900-10, 2006 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-16952558

RESUMEN

BACKGROUND & AIMS: The endogenous opioid system is involved in modulating the experience of pain, the response to stress, and the action of analgesic therapies. Recent human imaging studies have shown a significant tonic modulation of visceral pain, raising the question of whether endogenous opioids tonically modulate the pain of visceral cancer. METHODS: Transgenic mice expressing the first 127 amino acids of simian virus 40 large T antigen, under the control of the rat elastase-1 promoter, that spontaneously develop pancreatic cancer were used to investigate the role of endogenous opioids in the modulation of pancreatic cancer pain. Visceral pain behaviors were assessed as degree of hunching and vocalization. RESULTS: Although mice with late-stage pancreatic cancer displayed spontaneous, morphine-reversible, visceral pain-related behaviors such as hunching and vocalization, these behaviors were absent in mice with early-stage pancreatic cancer. After systemic administration of the central nervous system (CNS)-penetrant opioid receptor antagonists naloxone or naltrexone, mice with early-stage pancreatic cancer displayed significant visceral pain-related behaviors, whereas systemic administration of the CNS-nonpenetrant opioid antagonist naloxone-methiodide did not induce an increase in visceral pain behaviors. CONCLUSIONS: Our findings suggest that a CNS opioid-dependent mechanism tonically modulates early and late-stage pancreatic cancer pain. Understanding the mechanisms that mask this pain in early stage disease and drive this pain in late-stage disease may allow improved diagnosis, treatment, and care of patients with pancreatic cancer.


Asunto(s)
Dolor Abdominal/tratamiento farmacológico , Neurotransmisores/uso terapéutico , Péptidos Opioides/uso terapéutico , Neoplasias Pancreáticas/complicaciones , Dolor Abdominal/etiología , Dolor Abdominal/metabolismo , Animales , Modelos Animales de Enfermedad , Femenino , Inmunohistoquímica , Masculino , Ratones , Naloxona/farmacología , Antagonistas de Narcóticos/farmacología , Dimensión del Dolor , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/patología , Índice de Severidad de la Enfermedad , Resultado del Tratamiento
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