Antinociceptive effect of a genomic herpes simplex virus-based vector expressing human proenkephalin in rat dorsal roof ganglion

Endogenous opiate peptides acting pre- and post-synaptically in the dorsal horn of spinal cord inhibit transmission of nociceptive stimuli. We transfe cted neurons of the dorsal root ganglion in vivo by footpad inoculation wit h 30 mul (3 x 10(7) p.f.u.) of a replication-incompetent (ICP4-deleted) her pes simplex virus (HSV) vector with a cassette containing a portion of the human proenkephalin gene coding for 5 metand 1 leu-enkephalin molecules und er the control of the human cytomegalovirus immediate-early promoter (HCMV IEp) inserted in the HSV thymidine kinase (tk) locus. Vector-directed expre ssion of enkephalin produced a significant antinociceptive effect measured by the formalin footpad test, that was most prominent in the delayed ('toni c') phase 20-70 min after the administration of formalin. The magnitude of the antinociceptive effect diminished over 4 weeks after transduction, but reinoculation of the vector reestablished the analgesic effect, without evi dence for the development of tolerance. The antinociceptive effect was bloc ked completely by intrathecal naltrexone, These results suggest that gene t herapy with an enkephalin-producing herpes-based vector may prove useful in the treatment of pain.