dsAAV type 2-mediated gene transfer of MORS196A-EGFP into spinal cord as a pain management paradigm

S. L. Chen, H. I. Ma, J. M. Han, P. L. Tao, P. Y. Law, H. H. Loh

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

We previously reported that mutations in the μ-opioid receptor (MOR), S196L or S196A, rendered MOR responsive to the opioid antagonist naloxone without altering the agonist phenotype. Subsequently, a mouse strain carrying the S196A mutation exhibited in vivo naloxone antinociceptive activity without the development of tolerance. In this study we investigated the possibility of combining the in vivo site-directed delivery of MORS196A and systemic naloxone administration as a paradigm for pain management. Double-stranded adenoassociated virus type 2 (dsAAV2) was used to deliver MORS196A-EGFP by injecting the virus into the spinal cord (S2/S3) dorsal horn region of ICR mice. MORS196A-EGFP fluorescence colocalized with some calcitonin gene-related peptide and neuron-specific protein immunoreactivity in the superficial layers of the dorsal horn 1 week after injection and lasted for at least 6 months. In mice injected with the mutant receptor, morphine induced similar antinociceptive responses and tolerance development or precipitated withdrawal symptoms and reward effects, similar to those in the control mice (saline injected into the spinal cord). Conversely, in the dsAAV2-injected mice, naloxone produced antinociceptive effects at the spinal level but not at the supraspinal level, whereas naloxone had no measurable effect on the control mice. Furthermore, the chronic administration of naloxone to mice injected with dsAAV2-MORS196A-EGFP did not induce tolerance, dependence, or reward responses. Thus, our current approach to activate a mutant receptor, but not the endogenous receptor, with an opioid antagonist represents an alternative to the use of traditional opioid agonists for pain management.

Original languageEnglish (US)
Pages (from-to)20096-20101
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume104
Issue number50
DOIs
StatePublished - Dec 11 2007

Keywords

  • Morphine
  • Naloxone
  • μ-opioid receptor

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