title: 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.
authors.affiliation: Department of Psychology & the Center for Neuroscience, University of CO at Boulder, Boulder, CO 80309, USA. emilligan@psych.colorado.edu
authors.forename: Erin D
authors.initials: ED
authors.lastname: Milligan
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Langer
authors.forename: Evan M
authors.initials: EM
authors.lastname: Sloane
authors.forename: Lin
authors.initials: L
authors.lastname: He
authors.forename: Julie
authors.initials: J
authors.lastname: Wieseler-Frank
authors.forename: Kevin
authors.initials: K
authors.lastname: O'Connor
authors.forename: David
authors.initials: D
authors.lastname: Martin
authors.forename: John R
authors.initials: JR
authors.lastname: Forsayeth
authors.forename: Steven F
authors.initials: SF
authors.lastname: Maier
authors.forename: Kirk
authors.initials: K
authors.lastname: Johnson
authors.forename: Raymond A
authors.initials: RA
authors.lastname: Chavez
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Leinwand
authors.forename: Linda R
authors.initials: LR
authors.lastname: Watkins
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001522:Behavior, Animal; D004305:Dose-Response Relationship, Drug; D007839:Functional Laterality / Q000502:physiology; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006614:Hindlimb / Q000187:drug effects / Q000294:innervation / Q000503:physiopathology; D006801:Humans; D007278:Injections, Spinal / Q000379:methods; D007375:Interleukin-1 / Q000096:biosynthesis / Q000627:therapeutic use; D016753:Interleukin-10 / Q000096:biosynthesis / Q000134:cerebrospinal fluid / Q000235:genetics / Q000627:therapeutic use*; D008297:Male; D008845:Microinjections / Q000379:methods; D010146:Pain / Q000145:classification / Q000209:etiology; D059408:Pain Management; D010147:Pain Measurement / Q000379:methods; D017288:Pain Threshold / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017472:Receptors, Interleukin-1 / Q000008:administration & dosage; D053573:Receptors, Interleukin-1 Type I; D013997:Time Factors; D015054:Zymosan / Q000627:therapeutic use
chemical_list: D007375:Interleukin-1; D017472:Receptors, Interleukin-1; D053573:Receptors, Interleukin-1 Type I; D016753:Interleukin-10; D015054:Zymosan