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

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 paclitaxelinduced neuropathic pain.

Glia in pathological pain: A role for fractalkine

“…Nitric oxide was found to be key in mediating elevations of IL1, TNF and IL6 mRNA and protein in lumbar spinal cord leading to allodynia in gp120-treated animals (Holguin et al, 2004). In addition, IL-1 was shown to be important for the maintenance of neuropathic pain states because established neuropathic pain can be reversed either by proinflammatory cytokine antagonists or by the anti-inflammatory cytokine interleukin-10 (IL10) (Abraham et al, 2004, Johnston et al, 2004, Ledeboer et al, 2007, Milligan et al, 2005a, Milligan et al, 2005b, Milligan et al, 2006a, Milligan et al, 2006b, Plunkett et al, 2001, Sloane et al, submitted, Yu et al, 2003 that inhibits the production and activity of proinflammatory cytokines ). Such results are important when one is considering the potential of targeting proinflammatory cytokines for clinical pain control.…”

“…Gene-encoding vectors, such as viral and non-viral vectors to deliver the IL-2, IL-4 or IL-10 gene to the spinal cord to control pain in neuropathic rodent models have been examined and show promise (Hao et al, 2006, Ledeboer et al, 2007, Milligan et al, 2005a, Milligan et al, 2005b, Yao et al, 2003, Yao et al, 2002a, Yao et al, 2002b. For example, spinal cord over-expression of IL-10 controls pain produced by sciatic inflammatory neuropathy and chronic constriction injury (Milligan et al, 2005a, Milligan et al, 2007, Milligan et al, 2005b. The duration of pain control by spinal IL-10 gene therapy was observed from 1-3 months (Milligan et al, 2006a, Sloane et al, submitted).…”

“…Allodynia was completely reversed for several days (Fig 1). Additionally, the therapeutic benefit of spinal IL-10 over expression via gene therapy extended to other clinically relevant pain problems such as a rodent model for cancer chemotheraputic pain which attenuated allodynia for greater than 35 days (Ledeboer et al, 2007). Thus, pathological pain states can be controlled by spinal application of antiinflammatory cytokines that act block glial proinflammatory activity.…”

Intrathecal herpes simplex virus type 1 amplicon vector-mediated human proenkephalin reduces chronic constriction injury-induced neuropathic pain in rats

“…intrathecal (i.t.) delivery is a commonly used method for chronic pain gene therapy (15)(16)(17)(18). hPPe delivered i.t.…”

Transient Receptor Potential Channels in Chemotherapy-Induced Neuropathy

“…LC cells may contribute to pain development by different mechanisms including release of nitric oxide (NO) [45], proinflammatory cytokines [46], and neurotrophic factors [47], that in turn cause spontaneous neuronal discharge, nociceptor sensitization, and mechano-hypersensitivity. It has also been demonstrated that paclitaxel-induced neuropathic pain is associated with TNF-and IL-1 induction in lumbar DRGs [48]. Glial cell inhibitors attenuate paclitaxel-and vincristine-induced neuropathic pain [49,50], supporting a role for activated glial cells in this condition.…”