Antihyperalgesic effects of infection with a preproenkephalin-encoding herpes virus

To test the utility of gene therapeutic approaches for the treatment of pai n, a recombinant herpes simplex virus, type 1, has been engineered to conta in the cDNA for an opioid peptide precursor, human preproenkephalin, under control of the human cytomegalovirus promoter, This virus and a similar rec ombinant containing the Escherichia coli lacZ gene were applied to the abra ded skin of the dorsal hindpaw of mice, After infection, the presence of P- galactosidase in neuronal cell bodies of the relevant spinal ganglia (lacZ- containing virus) and of human proenkephalin (preproenkepbalin-encoding vir us) in the central terminals of these neurons indicated appropriate gene de livery and expression. Baseline foot withdrawal responses to noxious radian t heat mediated by A delta and C fibers were similar in animals infected wi th proenkephalin-encoding and P-galactosidase-encoding viruses. Sensitizati on of the foot withdrawal response after application of capsaicin (C fibers ) or dimethyl sulfoxide (A delta fibers) observed in control animals was re duced or eliminated in animals infected with the proenkephalin-encoding vir us for at least 7 weeks postinfection, Hence, preproenkephalin cDNA deliver y selectively blocked hyperalgesia without disrupting baseline sensory neur otransmission, This blockade of sensitization was reversed by administratio n of the opioid antagonist naloxone, apparently acting in the spinal cord, The results demonstrate that the function of sensory neurons can be selecti vely altered by viral delivery of a transgene, Because hyperalgesic mechani sms may be important in establishing and maintaining neuropathic and other chronic pain states, this approach may be useful for treatment of chronic p ain and hyperalgesia in humans.