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

Abstract

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.

• Authors: Erin D Milligan, Evan M Sloane, Stephen J Langer, Travis S Hughes, Brian M Jekich, Matthew G Frank, John H Mahoney, Lindsay H Levkoff, Steven F Maier, Pedro E Cruz, Terence R Flotte, Kirk W Johnson, Melissa M Mahoney, Raymond A Chavez, Leslie A Leinwand, Linda R Watkins
• Journal: Pain (Pain) Vol. 126 Issue 1-3 Pg. 294-308 (Dec 15 2006) ISSN: 1872-6623 [Electronic] United States
• PMID: 16949747 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Interleukin-10
• DNA

Topics

• Animals
• DNA (administration & dosage, cerebrospinal fluid, pharmacokinetics, therapeutic use)
• Drug Administration Schedule
• Genetic Therapy
• Humans
• Hyperesthesia (etiology, physiopathology, therapy)
• Injections, Spinal
• Interleukin-10 (genetics)
• Ligation
• Male
• Microinjections
• Neuralgia (physiopathology, therapy)
• Plasmids (administration & dosage, cerebrospinal fluid, pharmacokinetics, therapeutic use)
• Rats
• Rats, Sprague-Dawley
• Sciatic Nerve
• Spinal Cord (metabolism)
• Time Factors
• Tissue Distribution