Repeated intrathecal injections of plasmid DNA encoding interleukin-10 produce prolonged reversal of neuropathic pain.
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.
Milligan
Erin D
ED
Department of Psychology and the Center for Neuroscience, University of CO at Boulder, Boulder, CO 80309, USA. erin.milligan@colorado.edu
Sloane
Evan M
EM
Langer
Stephen J
SJ
Hughes
Travis S
TS
Jekich
Brian M
BM
Frank
Matthew G
MG
Mahoney
John H
JH
Levkoff
Lindsay H
LH
Maier
Steven F
SF
Cruz
Pedro E
PE
Flotte
Terence R
TR
Johnson
Kirk W
KW
Mahoney
Melissa M
MM
Chavez
Raymond A
RA
Leinwand
Leslie A
LA
Watkins
Linda R
LR
D000818:Animals; D004247:DNA / Q000008:administration & dosage* / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics / Q000627:therapeutic use; D004334:Drug Administration Schedule; D015316:Genetic Therapy; D006801:Humans; D006941:Hyperesthesia / Q000209:etiology / Q000503:physiopathology / Q000628:therapy; D007278:Injections, Spinal; D016753:Interleukin-10 / Q000235:genetics*; D008026:Ligation; D008297:Male; D008845:Microinjections; D009437:Neuralgia / Q000503:physiopathology* / Q000628:therapy*; D010957:Plasmids / Q000008:administration & dosage* / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D012584:Sciatic Nerve; D013116:Spinal Cord / Q000378:metabolism; D013997:Time Factors; D014018:Tissue Distribution
D016753:Interleukin-10; D004247:DNA