Enhanced peripheral analgesia using virally mediated gene transfer of the μ-opioid receptor in mice

BACKGROUND: The use of opioids to treat pain is often limited by side effects mediated through the central nervous system. The current study used a recombinant herpes simplex virus type 1 to increase expression of the μ-opioid receptor (μOR) in primary afferent neurons. The goal of this strategy was to enhance peripheral opioid analgesia. METHODS: Cutaneous inoculation with herpes simplex virus containing μOR complementary DNA (cDNA) in antisense (SGAMOR) or sense (SGMOR) orientation relative to a constitutive promoter, or complementary DNA for Escherichia coli lac Z gene as a control virus (SGZ) was used to modify the levels of μOR in primary afferents. The effects of altered μOR levels on peripheral analgesia were then examined. RESULTS: At 4 weeks after SGAMOR and SGMOR infection, decreased and increased μOR immunoreactivity was observed in ipsilateral dorsal hind paw skin, lumbar dorsal root ganglion cells, and superficial dorsal horns, respectively, compared with SGZ. This change in μOR expression in mice by SGAMOR and SGMOR was accompanied at the behavioral level with a rightward and leftward shift in the loperamide dose-response curve, respectively, compared with SGZ. CONCLUSIONS: This gene therapy approach may provide an innovative strategy to enhance peripheral opioid analgesia for the treatment of pain in humans, thereby minimizing centrally mediated opioid side effects such as sedation and addiction.