Intrathecal interleukin-10 gene therapy attenuates paclitaxel-induced mechanical allodynia and proinflammatory cytokine expression in dorsal root ganglia in rats.
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.
Ledeboer
Annemarie
A
Department of Psychology & the Center for Neuroscience, University of Colorado at Boulder, Boulder, CO, USA. aledeboer@avigen.com
Jekich
Brian M
BM
Sloane
Evan M
EM
Mahoney
John H
JH
Langer
Stephen J
SJ
Milligan
Erin D
ED
Martin
David
D
Maier
Steven F
SF
Johnson
Kirk W
KW
Leinwand
Leslie A
LA
Chavez
Raymond A
RA
Watkins
Linda R
LR
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects*; D039481:CD11b Antigen / Q000187:drug effects / Q000378:metabolism; D016207:Cytokines / Q000187:drug effects / Q000276:immunology; D004195:Disease Models, Animal; D005727:Ganglia, Spinal / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D015316:Genetic Therapy / Q000379:methods; D006930:Hyperalgesia / Q000139:chemically induced / Q000209:etiology / Q000517:prevention & control*; D007278:Injections, Spinal; D016753:Interleukin-10 / Q000008:administration & dosage / Q000235:genetics / Q000502:physiology*; D053583:Interleukin-1beta / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008578:Meninges / Q000187:drug effects / Q000378:metabolism; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism; D017239:Paclitaxel / Q000009:adverse effects*; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced / Q000150:complications / Q000517:prevention & control*; D010957:Plasmids / Q000008:administration & dosage / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors / Q000502:physiology; D013116:Spinal Cord / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects / Q000378:metabolism
D000972:Antineoplastic Agents, Phytogenic; D039481:CD11b Antigen; D016207:Cytokines; D053583:Interleukin-1beta; D012333:RNA, Messenger; D017472:Receptors, Interleukin-1; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D017239:Paclitaxel