Repeated intrathecal injections of plasmid DNA encoding interleukin-10 produce prolonged reversal of neuropathic pain

Abstract

Neuropathic pain is a major clinical problem unresolved by available therapeutics. Spinal cord glia play a pivotal role in neuropathic pain, via the release of proinflammatory cytokines. Anti-inflammatory cytokines, like interleukin-10 (IL-10), suppress proinflammatory cytokines. Thus, IL-10 may provide a means for controlling glial amplification of pain. We recently documented that intrathecal IL-10 protein resolves neuropathic pain, albeit briefly (approximately 2-3 h), given its short half-life. Intrathecal gene therapy using viruses encoding IL-10 can also resolve neuropathic pain, but for only approximately 2 weeks. Here, we report a novel approach that dramatically increases the efficacy of intrathecal IL-10 gene therapy. Repeated intrathecal delivery of plasmid DNA vectors encoding IL-10 (pDNA-IL-10) abolished neuropathic pain for greater than 40 days. Naked pDNA-IL-10 reversed chronic constriction injury (CCI)-induced allodynia both shortly after nerve injury as well as 2 months later. This supports that spinal proinflammatory cytokines are important in both the initiation and maintenance of neuropathic pain. Importantly, pDNA-IL-10 gene therapy reversed mechanical allodynia induced by CCI, returning rats to normal pain responsiveness, without additional analgesia. Together, these data suggest that intrathecal IL-10 gene therapy may provide a novel approach for prolonged clinical pain control.

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

“…intrathecal delivery of recombinant adeno-associated virus expressing the anti-inflammatory gene product human IL-10 or brain-derived neurotrophic factor has been shown to attenuate chronic neuropathic pain after partial nerve injury (32)(33)(34). These studies indicate that the i.t.…”

Posttraumatic stress disorder influences the nociceptive and intrathecal cytokine response to a painful stimulus in combat veterans

“…IL-10 then activates STAT3 signaling by IL-10 receptors 1 and 2, resulting in decreased synthesis of multiple cytokines, including TNF␣, IL-1␤, and IL-6 (de Waal Malefyt et al, 1991;Murray, 2005;Sabat et al, 2010). Supporting the anti-nociceptive and anti-inflammatory properties of IL-10, the administration of exogenous IL-10: 1) decreases TNF␣ induced hyperalgesia and 2) produces prolonged reversal of neuropathic pain when administered in the intrathecal space (Milligan et al, 2006a;Milligan et al, 2006b;Wagner et al, 1998). Clinical research has documented further that there are significantly lower levels of IL-10 in the CSF of patients with chronic pain as compared to age-matched healthy controls (Backonja et al, 2008).…”

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.…”