Intrathecal interleukin-10 gene therapy attenuates paclitaxel-induced mechanical allodynia and proinflammatory cytokine expression in dorsal root ganglia in rats

• Published in: Brain, behavior, and immunity Vol. 21; no. 5; pp. 686 - 698
• Main Authors: Ledeboer, Annemarie, Jekich, Brian M, Sloane, Evan M, Mahoney, John H, Langer, Stephen J, Milligan, Erin D, Martin, David, Maier, Steven F, Johnson, Kirk W, Leinwand, Leslie A, Chavez, Raymond A, Watkins, Linda R
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 01.07.2007
• Subjects: Allergy and Immunology; Animals; Antineoplastic Agents, Phytogenic - adverse effects; CD11b Antigen - drug effects; CD11b Antigen - metabolism; Cytokines - drug effects; Cytokines - immunology; Disease Models, Animal; Ganglia, Spinal - cytology; Ganglia, Spinal - drug effects; Ganglia, Spinal - metabolism; Genetic Therapy - methods; Glia; Hyperalgesia - chemically induced; Hyperalgesia - etiology; Hyperalgesia - prevention & control; Injections, Spinal; Interleukin-1; Interleukin-10 - administration & dosage; Interleukin-10 - genetics; Interleukin-10 - physiology; Interleukin-1beta - drug effects; Interleukin-1beta - metabolism; Macrophages; Male; Meninges; Meninges - drug effects; Meninges - metabolism; Neuroglia - drug effects; Neuroglia - metabolism; Neuropathic pain; Paclitaxel - adverse effects; Pain Threshold - drug effects; Pain Threshold - physiology; Peripheral Nervous System Diseases - chemically induced; Peripheral Nervous System Diseases - complications; Peripheral Nervous System Diseases - prevention & control; Plasmids - administration & dosage; Plasmids - genetics; Psychiatry; Rats; Rats, Sprague-Dawley; Receptors, Interleukin-1 - antagonists & inhibitors; Receptors, Interleukin-1 - physiology; RNA, Messenger - analysis; Spinal Cord - cytology; Spinal Cord - drug effects; Spinal Cord - metabolism; Tumor necrosis factor; Tumor Necrosis Factor-alpha - drug effects; Tumor Necrosis Factor-alpha - metabolism; Interleukin-1; Meninges; Glia; Macrophages; Tumor necrosis factor; Neuropathic pain
• ISSN: 0889-1591; 1090-2139
• DOI: 10.1016/j.bbi.2006.10.012

Abstract 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.