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Controlling pathological pain by adenovirally driven spinal production of the anti-inflammatory cytokine, interleukin-10
- Erin D. Milligan 1 1Department of Psychology & the Center for Neuroscience, University of CO at Boulder, Boulder, CO 80309, USA ,
- Stephen J. Langer 2 2Department of Molecular, Cellular & Developmental Biology, University of CO at Boulder, Boulder, CO 80309, USA ,
- Evan M. Sloane 1 1Department of Psychology & the Center for Neuroscience, University of CO at Boulder, Boulder, CO 80309, USA ,
- Lin He 3 3Avigen, Alameda, CA 94502, USA ,
- Julie Wieseler-Frank 1 1Department of Psychology & the Center for Neuroscience, University of CO at Boulder, Boulder, CO 80309, USA ,
- Kevin O'Connor 1 1Department of Psychology & the Center for Neuroscience, University of CO at Boulder, Boulder, CO 80309, USA ,
- David Martin 4 4Dept of Pharmacology, Amgen, Thousand Oaks, CA 21320, USA ,
- John R. Forsayeth 3 3Avigen, Alameda, CA 94502, USA ,
- Steven F. Maier 1 1Department of Psychology & the Center for Neuroscience, University of CO at Boulder, Boulder, CO 80309, USA ,
- Kirk Johnson 3 3Avigen, Alameda, CA 94502, USA ,
- Raymond A. Chavez 3 3Avigen, Alameda, CA 94502, USA ,
- Leslie A. Leinwand 2 2Department of Molecular, Cellular & Developmental Biology, University of CO at Boulder, Boulder, CO 80309, USA and
- Linda R. Watkins 1 1Department of Psychology & the Center for Neuroscience, University of CO at Boulder, Boulder, CO 80309, USA
E-mail: emilligan@psych.colorado.edu
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 (t1/2 
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.
This article is cited by:
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