Studies show that spinal (intrathecal; i.t.)
interleukin-10 (IL-10) gene therapy reverses
neuropathic pain in animal models, and co-administration with the
mannose receptor (MR; CD206)
ligand d-mannose (DM) greatly improves therapeutic efficacy. However, the actions of endogenous
IL-10 may be required for enduring
pain control observed following i.t.
IL-10 gene therapy, potentially narrowing the application of this non-viral transgene delivery approach. Here, we show that i.t. application of naked plasmid
DNA expressing the
IL-10 transgene co-injected with DM (DM/pDNA-IL-10) for the treatment of peripheral
neuropathic pain in
IL-10 deficient (IL-10 KO) mice results in a profound and prolonged bilateral
pain suppression.
Neuropathic pain is induced by unilateral sciatic chronic constriction injury (CCI), and while enduring relief of light touch sensitivity (
mechanical allodynia) in both wild type (WT) and
IL-10 KO mice was observed following DM/pDNA-IL-10 co-
therapy, transient reversal from
allodynia was observed following i.t. DM alone. In stably
pain-relieved
IL-10 KO mice given DM/pDNA-IL-10,
mRNA for the
IL-10 transgene is detected in the cauda equina and ipsilateral dorsal root ganglia (DRG), but not the lumbar spinal cord. Further, DM/pDNA-IL-10 application increases anti-inflammatory TGF-β1 and decreases pro-inflammatory TNF
mRNA in the ipsilateral DRG compared to allodynic controls. Additionally, DM/pDNA-IL-10 treated mice exhibit decreased spinal pro-inflammatory
mRNA expression for TNF, CCL2 (MCP-1), and for the microglial-specific marker TMEM119. Similarly, DM/pDNA-IL-10 treatment decreases immunoreactivity for the astrocyte activation marker GFAP in lumbar spinal cord dorsal horn. Despite transient reversal and early return to
allodynia in DM-treated mice, lumbar spinal cord revealed elevated TNF, CCL2 and TMEM119
mRNA levels. Both MR (CD206) and
IL-10 receptor mRNAs are increased in the DRG following CCI manipulation independent of injection treatment, suggesting that pathological conditions stimulate upregulation and availability of relevant receptors in critical anatomical regions required for the therapeutic actions of the DM/pDNA-IL-10 co-
therapy. Taken together, the current report demonstrates that non-viral DM/pDNA-IL-10 gene therapy does not require endogenous
IL-10 for enduring relief of peripheral
neuropathic pain and does not require direct contact with the spinal cord dorsal horn for robust and enduring relief of
neuropathic pain. Spinal non-viral DM/pDNA-IL-10 co-
therapy may offer a framework for the development of non-viral gene therapeutic approaches for other diseases of the central nervous system.