Evan M. Sloane

University of Colorado Boulder

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Linda R. Watkins

University of Colorado Boulder

Erin D. Milligan

University of New Mexico

Steven F. Maier

University of Colorado Boulder

Leslie A. Leinwand

University of Colorado Boulder

Stephen J. Langer

University of Colorado Boulder

Raymond A. Chavez

Tel Aviv Sourasky Medical Center

John H. Mahoney

Pfizer (United States)

Brian Jekich

Colorado Permanente Medical Group

Julie Wieseler‐Frank

University of Colorado Boulder

Kirk W. Johnson

Eli Lilly (United States)

Cooperative Institutions

University of Colorado Boulder

Center for Neurosciences

University of Colorado System

University of New Mexico

Xalud Therapeutics (United States)

National Institutes of Health

University of California, San Diego

University of Colorado Denver

Epigen Biosciences (United States)

Netherlands Institute for Neuroscience

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Peri-sciatic proinflammatory cytokines, reactive oxygen species, and complement induce mirror-image neuropathic pain in rats

Pain (2004)

Carin Twining Evan M. Sloane Erin D. Milligan Marucia Chacur David E. Martin

In inflammatory neuropathy, immune activation near intact peripheral nerves induces mechanical allodynia. The identity of the peripheral immune product(s) that lead to these changes in pain behavior is unknown. The present series of studies utilized the sciatic inflammatory neuropathy (SIN) model to examine this question. Here, inflammatory neuropathy is created by injecting an immune activator (zymosan) around one sciatic nerve via an indwelling catheter. Our prior studies demonstrated that peri-sciatic zymosan activated macrophages and neutrophils to release proinflammatory cytokines and reactive oxygen species (ROS). In addition, zymosan is a classical activator of the complement cascade. Thus the present series of experiments examined whether any of these inflammatory mediators are involved in the initial induction of SIN-induced ipsilateral or bilateral allodynias. Peri-sciatic injection of selective inhibitors/antagonists revealed that a number of immune products are early mediators of the resultant allodynias, including proinflammatory cytokines (tumor necrosis factor, interleukin-1, and interleukin-6), ROS, and complement. Thus these immune-derived substances can markedly alter sensory nerve function at mid-axon.

Proinflammatory cytokine

Zymosan

Axon reflex

10.1016/j.pain.2004.04.008

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Citations (130)

Animal Models of Chronic Pain

Journal of Pain (2004)

Erin D. Milligan Stephen J. Langer Evan M. Sloane Julie Wieseler‐Frank Matthew G. Frank

Proinflammatory cytokine

Allodynia

10.1016/j.jpain.2004.02.029

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Adenosine 2A receptor agonist produces long-duration reversal of neuropathic pain via sustained release of spinal interleukin-10

Journal of Pain (2009)

Lisa C. Loram Paige W. Sholar Frederick R. Taylor Jackie Harrison Mark R. Hutchinson

Allodynia

Adenosine A2A receptor

10.1016/j.jpain.2009.01.165

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260. ITRs Necessary for IL-10 Encoding Naked Plasmid Induced Reversal of Chronic Pain State in Rat

Molecular Therapy (2006)

Travis Hughes Stephen J. Langer Evan M. Sloane John H. Mahoney Brian Jekich

Controlling chronic pain in humans is a major unresolved problem. Spinal cord astrocytes and microglia are critically involved in the creation and maintenance of diverse enhanced pain states via the release of proinflammatory cytokines. Interluekin-10 (IL-10), a potent anti-inflammatory cytokine, suppresses proinflammatory cytokine production and activity. Control of chronic neuropathic pain such as sensitivity to light touch (allodynia) requires chronic spinal delivery of IL-10. Chronic pain can be surgically induced in rats by loose ligature of chromic cat gut around the sciatic nerve in four places. This creates a chronic constriction injury (CCI) as the nerve bundle swells against the irritating ligature. The CCI model produces an enhanced pain phenotype for 3 months. We have demonstrated that this pain is reversed transiently (4hrs.) through intrathecal injection of recombinant IL-10 protein and that two temporally spaced injections of an IL-10 expression vector containing inverted terminal repeats (ITRs) reverses this pain long term (3+ months, Milligan et al., these proceedings). The role of ITRs in gene expression is not well known, however there is evidence that they possess transcription promoter and enhancer activity (Flotte et al., 1992 Am J Respir Cell Mol Biol. 7:p349-56 and 1993 J Biol Chem. 268: p3781-90). Based on this and other evidence in the literature we sought to determine if the ITRs in our expression vector, which are located 5|[prime]| of the CMV enhancer and Chicken |[beta]|-actin promoter (5|[prime]| ITR) and 3|[prime]| of the SV 40 poly A tail sequence (3|[prime]| ITR), influence reversal of pain in the CCI model. To this end we deleted both ITR's from the expression vector and found that it was incapable of producing pain reversal. We next asked if one or both ITRs are necessary for pain reversal. We found that plasmids containing just the 3|[prime]| or 5|[prime]| ITR are not as robust in reversing chronic pain. We have also found that ITRs are required on the first injection but not on a second injection for long-term pain relief. In other words, initial injection of a plasmid containing ITRs seems to |[ldquo]|prime|[rdquo]| the system making the second injection of the expression vector vastly more efficacious. Ongoing studies seek to further characterize the role of ITRs on gene expression and pain reversal in the CCI model.

10.1016/j.ymthe.2006.08.287

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

Pain (2006)

Erin D. Milligan Evan M. Sloane Stephen J. Langer Travis Hughes Brian Jekich

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

Interleukin 1β

10.1016/j.pain.2006.07.009

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Citations (176)

Activation of the spinal cord complement cascade might contribute to mechanical allodynia induced by three animal models of spinal sensitization

Journal of Pain (2005)

Carin Twining Evan M. Sloane D. Schoeniger Erin D. Milligan David Martin

Allodynia

10.1016/j.jpain.2004.11.011

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Citations (56)

Long-term control of neuropathic pain in a non-viral gene therapy paradigm

Gene Therapy (2009)

Evan M. Sloane Ryan G. Soderquist Steven F. Maier Melissa J. Mahoney Linda R. Watkins

10.1038/gt.2009.21

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Citations (35)

259. Plasmid DNA Encoding the Anti-Inflammatory Cytokine Gene, Interleukin-10 (IL-10) for Chronic Pain Control: Taking Advantage of Nuclear Scaffold/Matrix Attachment Regions

Molecular Therapy (2006)

Erin D. Milligan Stephen J. Langer Travis Hughes Evan M. Sloane John H. Mahoney

Chronic pathological pain is a major unresolved clinical problem. Spinal cord glial cells are important in diverse forms of enhanced pain states via their release of proinflammatory cytokines. Interleukin-10 (IL-10), a potent anti-inflammatory cytokine, suppresses proinflammatory cytokine production & activity. We have shown that spinal delivery (intrathecal; i.t.) of IL-10 protein resolves animal models of pathological pain. Both i.t. IL-10 protein or i.t. viral vector-delivered IL-10 gene lead to transient therapeutic effects (2hr & 2 wk, respectively). We have recently reported that i.t. naked plasmid DNA encoding IL-10 (pDNA-IL-10) leads to a substantial improvement in the duration of therapeutic pain control (40 days). However, transgene IL-10 may be compromised &/or cleared by cell division. Recently, a chromosomal scaffold/matrix- attached region (S/MAR) linked to the simian virus 40 origin of replication was reported to stably propagate episomally in mammalian cells. Mitotic stability occurs via specific interactions with nuclear matrix proteins. We sought determine if S/MAR inserted into our current plasmid (pDNA-S/MARS-IL10) could improve upon the therapeutic duration of pain control in an animal model of neuropathic pain. The model we use is hypersensitivity to light touch [allodynia] produced by chronic constriction injury [CCI] of the sciatic nerve. Naked pDNA-S/MARS-IL10 was injected peri- spinally (intrathecally; i.t.) after CCI-sensitivity was induced. Behavioral measures were assessed in rats prior to & at 3 & 10 days after induction of CCI. Intrathecal injections were given on Day 10 & Day 12 post-CCI consisting of pDNA-S/MARS-IL10 (100 ug/injection in 18 ul), or pDNA-IL-10 (100 ug/injection in 18 ul). A second i.t. pDNA-S/MARS-IL10 (1 or 25 ug/injection in 5 ul), or pDNA-IL10 (25 ug in 5 ul) injection was given 2 days later. Allodynia was reassessed every 4 days following the second DNA injection. Allodynia was stable through day 10 after CCI induction. An immediate & robust improvement of pain reversal was observed within 24 hr after the first injection of pDNA-S/MARS-IL10 vs pDNA-IL-10. Animals have remained reversed from CCI-induced allodynia after the second i.t. pDNA-S/MARS-IL10 and 25 ug is most effective.Studies are ongoing and will be terminated 90 days after CCI or when CCI-induced allodynia returns. Simultaneous studies are determining whether 1) a single i.t. injection of pDNA-S/ MARS-IL10 is sufficient for long-term pain control, 2) transgene expression by protein analysis can be detected at 1, 2 &/or 3 months in cerebrospinal fluid after injection in behaviorally verified rats, and 3) the distribution of transgene expression in superficial spinal cord or deeper parenchymal layers. We thank Dr. Hans J. Lipps for the gift of plasmid containing pDNA-S/MARS. Support: NIH HL56510, DA018156 & DA015642.

Proinflammatory cytokine

10.1016/j.ymthe.2006.08.286

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Citations (1)

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

Brain Behavior and Immunity (2006)

Annemarie Ledeboer Brian Jekich Evan M. Sloane John H. Mahoney Stephen J. Langer

Proinflammatory cytokine

Allodynia

10.1016/j.bbi.2006.10.012

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Citations (301)

530. Spinal Interleukin-10 (IL-10) Gene Therapy Using Viral and Non-Viral Vectors Controls Inflammatory- and Chronic Constriction Injury-Induced Pain States in Rats

Molecular Therapy (2004)

Erin D. Milligan Raymond A. Chavez Stephen J. Langer Evan M. Sloane Maru Chacur

Spinal cord glia, via proinflammatory cytokines (interleukin-1, tumor necrosis factor, & interleukin-6), critically mediate the creation/maintenance of pathological pain such as sciatic inflammatory neuropathy (SIN) & chronic constriction injury (CCI). The anti-inflammatory cytokine, IL-10, suppresses proinflammatory cytokine production & function. We have used a variety of gene therapy approaches to examine the efficacy of IL-10 in rat models of neuropathic pain. Behavior was assessed before & after induction of various pain models. Adenoviral vectors expressing the IL-10 gene block &/or reverse exaggerated pain (mechanical allodynia [von Frey test] & thermal hyperalgesia [Hargreaves test]) produced by intrathecal (IT) lumbosacral spinal (LS) delivery of gp120, SIN, & CCI. IT LS delivery of AAV2 encoding IL-10 (AAV2-IL-10) was able to block SIN allodynia [amp] reverse CCI allodynia [amp] thermal hyperalgesia. However, the effects of viral IL-10 delivery systems resulted in reversals in the pain state of short duration. An IL-10-encoding non-viral plasmid vector (NVV) was also introduced IT in the CCI model. In contrast to the viral vectors, this approach resulted in long-lasting reversals of the pain state. Ongoing experiments will assess additional effects of NVV-driven IL-10 protein expression, including the identification of transfected tissue(s). These results suggest that NVV-based IL-10 gene therapy may be a potent addition to the treatments available to neuropathic pain patients.

10.1016/j.ymthe.2004.06.477

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