Controlling pathological pain by adenovirally driven spinal production of the anti‐inflammatory cytokine, interleukin‐10

Abstract

Gene therapy for the control of pain has, to date, targeted neurons. However, recent evidence supports that spinal cord glia are critical to the creation and maintenance of pain facilitation through the release of proinflammatory cytokines. Because of the ability of interleukin-10 (IL-10) to suppress proinflammatory cytokines, we tested whether an adenoviral vector encoding human IL-10 (AD-h-IL10) would block and reverse pain facilitation. Three pain models were examined, all of which are mediated by spinal pro-inflammatory cytokines. Acute intrathecal administration of rat IL-10 protein itself briefly reversed chronic constriction injury-induced mechanical allodynia and thermal hyperalgesia. The transient reversal caused by IL-10 protein paralleled the half-life of human IL-10 protein in the intrathecal space (t(1/2) approximately 2 h). IL-10 gene therapy both prevented and reversed thermal hyperalgesia and mechanical allodynia, without affecting basal responses to thermal or mechanical stimuli. Extra-territorial, as well as territorial, pain changes were reversed by this treatment. Intrathecal AD-h-IL10 injected over lumbosacral spinal cord led to elevated lumbosacral cerebrospinal fluid (CSF) levels of human IL-10, with far less human IL-10 observed in cervical CSF. In keeping with IL-10's known anti-inflammatory actions, AD-h-IL10 lowered CSF levels of IL-1, relative to control AD. These studies support that this gene therapy approach provides an alternative to neuronally focused drug and gene therapies for clinical pain control.

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).…”

Viral Vector-based Gene Transfer for Treatment of Chronic Pain

“…18 In addition, intrathecal administration of the adenovirus expressing IL-10 prevented intrathecal HIV-1 gp 120-induced mechanical allodynia, without affecting basal responses to thermal or mechanical stimuli. 18 IL-2 is an important immuno-regulatory molecule in the central nervous system (CNS). 19,20 IL-2 and IL-2 receptors are widely distributed in rat CNS 21 and evidence showed that IL-2 had an antinociceptive effect in both central and peripheral nervous system 22 and inhibited nociceptive responses of spinal dorsal horn neurons.…”

“…4 Interleukin (IL)-10, an anti-inflammatory cytokine is known to suppress the production of proinflammatory cytokines. 17,18 Acute intrathecal administration of rat IL-10 protein itself briefly reverses sciatic chronic constriction injury (CCI)-induced mechanical allodynia and thermal hyperalgesia. 17,18 Watkins and coworkers demonstrated that intrathecal administration of adenoviral vector encoding for IL-10 injected over lumbosacral spinal cord led to elevated lumbosacral cerebrospinal fluid levels of IL-10, prevented sciatic nerve inflammation [sciatic inflammatory neuropathy (SIN)]-induced mechanical allodynia and attenuated chronic SINinduced territorial, extraterritoral, and mirror-imaging mechanical allodynia.…”

“…17,18 Acute intrathecal administration of rat IL-10 protein itself briefly reverses sciatic chronic constriction injury (CCI)-induced mechanical allodynia and thermal hyperalgesia. 17,18 Watkins and coworkers demonstrated that intrathecal administration of adenoviral vector encoding for IL-10 injected over lumbosacral spinal cord led to elevated lumbosacral cerebrospinal fluid levels of IL-10, prevented sciatic nerve inflammation [sciatic inflammatory neuropathy (SIN)]-induced mechanical allodynia and attenuated chronic SINinduced territorial, extraterritoral, and mirror-imaging mechanical allodynia. 18 In addition, intrathecal administration of the adenovirus expressing IL-10 prevented intrathecal HIV-1 gp 120-induced mechanical allodynia, without affecting basal responses to thermal or mechanical stimuli.…”