Intrathecal interleukin-10 gene therapy attenuates paclitaxel-induced mechanical allodynia and proinflammatory cytokine expression in dorsal root ganglia in rats
| Autor: | Erin D. Milligan, Stephen J. Langer, Leslie A. Leinwand, David Martin, Evan M. Sloane, Kirk W. Johnson, Brian M. Jekich, Raymond A. Chavez, Linda R. Watkins, Steven F. Maier, John H. Mahoney, Annemarie Ledeboer |
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| Rok vydání: | 2007 |
| Předmět: |
Male
Pain Threshold Paclitaxel medicine.medical_treatment Interleukin-1beta Immunology Pharmacology Article Proinflammatory cytokine Rats Sprague-Dawley Behavioral Neuroscience Meninges Ganglia Spinal Threshold of pain Animals Medicine RNA Messenger Injections Spinal CD11b Antigen Tumor Necrosis Factor-alpha Endocrine and Autonomic Systems business.industry Peripheral Nervous System Diseases Receptors Interleukin-1 Genetic Therapy Antineoplastic Agents Phytogenic Interleukin-10 Rats Disease Models Animal Interleukin 10 Cytokine Allodynia Spinal Cord Hyperalgesia Neuropathic pain Cytokines Tumor necrosis factor alpha medicine.symptom business Neuroglia Plasmids |
| Zdroj: | Brain, Behavior, and Immunity. 21:686-698 |
| ISSN: | 0889-1591 |
| Popis: | Paclitaxel is a commonly used cancer chemotherapy drug that frequently causes painful peripheral neuropathies. The mechanisms underlying this dose-limiting side effect are poorly understood. Growing evidence supports that proinflammatory cytokines, such as interleukin-1 (IL-1) and tumor necrosis factor (TNF), released by activated spinal glial cells and within the dorsal root ganglia (DRG) are critical in enhancing pain in various animal models of neuropathic pain. Whether these cytokines are involved in paclitaxel-induced neuropathy is unknown. Here, using a rat neuropathic pain model induced by repeated systemic paclitaxel injections, we examined whether paclitaxel upregulates proinflammatory cytokine gene expression, and whether these changes and paclitaxel-induced mechanical allodynia can be attenuated by intrathecal IL-1 receptor antagonist (IL-1ra) or intrathecal delivery of plasmid DNA encoding the anti-inflammatory cytokine, interleukin-10 (IL-10). The data show that paclitaxel treatment induces mRNA expression of IL-1, TNF, and immune cell markers in lumbar DRG. Intrathecal IL-1ra reversed paclitaxel-induced allodynia and intrathecal IL-10 gene therapy both prevented, and progressively reversed, this allodynic state. Moreover, IL-10 gene therapy resulted in increased IL-10 mRNA levels in lumbar DRG and meninges, measured 2 weeks after initiation of therapy, whereas paclitaxel-induced expression of IL-1, TNF, and CD11b mRNA in lumbar DRG was markedly decreased. Taken together, these data support that paclitaxel-induced neuropathic pain is mediated by proinflammatory cytokines, possibly released by activated immune cells in the DRG. We propose that targeting the production of proinflammatory cytokines by intrathecal IL-10 gene therapy may be a promising therapeutic strategy for the relief of paclitaxel-induced neuropathic pain. |
| Databáze: | OpenAIRE |
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