T raumatic injuries are often followed by chronic nerve pain that remains long after the original injury has healed. Drugs to treat such neuropathic pain are often ineffective and can be associated with severe side effects. Wilson ([1][1]), Iadarola ([2][2]), and their colleagues now report two similar strategies for treating chronic pain, using viruses to deliver genes encoding pain-killer proteins to the central nervous system. Unlike analgesic drugs that are administered systemically, targeted delivery of a therapeutic pain-killer gene ensures that its protein product will be secreted in the vicinity of the nerves that conduct pain impulses. To deliver the therapeutic gene to the spinal cord, the two groups developed different methods. Wilson and co-workers selected herpes simplex virus, which readily infects nerve cells, to transport the gene for human preproenkephalin (a precursor of Met-enkephalin, an opioid peptide with pain-killer activity) into mouse afferent nerves. They inoculated herpesvirus carrying the pain-killer gene into an abrasion in the mouse hindpaw. The virus traveled up the afferent nerves from the skin, taking up residence in the spinal cord. Here, proenkephalin was synthesized (red fluorescence in photo) and then processed into Met-enkephalin. Compared with mice inoculated with a marker gene, mice inoculated with the therapeutic gene took much longer to withdraw their hindpaw from a noxious stimulus, a measure of sensitivity to pain (hyperalgesia). Decreased pain sensitivity was observed for up to 6 weeks after inoculation of the therapeutic gene. That the pain-killing effect was at least partly due to Met-enkephalin was demonstrated by the restoration of hindpaw pain sensitivity after administration of naloxone, an opioid antagonist. ![Figure][3] CREDIT: REPRINTED WITH PERMISSION FROM PROC. NATL. ACAD. SCI. U.S.A. Iadarola's group took a different approach to deliver their therapeutic gene. They injected adenovirus—engineered to express the β-endorphin gene—directly into the cerebrospinal fluid (CSF) that bathes the spinal cord. β-endorphin (another pain-killer opioid peptide) was synthesized in the connective tissue cells of the pia mater (one of the membranes that protects the spinal cord). These cells secreted β-endorphin into the CSF. They found that injection of the therapeutic gene several days before testing resulted in a naloxone-reversible decrease in pain sensitivity. Although these effects were transient, when applied repeatedly this gene delivery strategy may be applicable to chronic pain in humans. 1. [↵][4]1. S. P. Wilson 2. et al. , Proc. Natl. Acad. Sci. U.S.A 96, 3211 (1999). [OpenUrl][5][Abstract/FREE Full Text][6] 2. [↵][7]1. A. A. Finegold, 2. A. J. Mannes, 3. M. J. Iadarola , Hum. Gene Ther. in press. [1]: #ref-1 [2]: #ref-2 [3]: pending:yes [4]: #xref-ref-1-1 View reference 1 in text [5]: {openurl}?query=rft.jtitle%253DPNAS%26rft.stitle%253DProc.%2BNatl.%2BAcad.%2BSci.%2BUSA%26rft.issn%253D0027-8424%26rft.aulast%253DWilson%26rft.auinit1%253DS.%2BP.%26rft.volume%253D96%26rft.issue%253D6%26rft.spage%253D3211%26rft.epage%253D3216%26rft.atitle%253DAntihyperalgesic%2Beffects%2Bof%2Binfection%2Bwith%2Ba%2Bpreproenkephalin-encoding%2Bherpes%2Bvirus%26rft_id%253Dinfo%253Adoi%252F10.1073%252Fpnas.96.6.3211%26rft_id%253Dinfo%253Apmid%252F10077663%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [6]: /lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6NDoicG5hcyI7czo1OiJyZXNpZCI7czo5OiI5Ni82LzMyMTEiO3M6NDoiYXRvbSI7czoyMzoiL3NjaS8yODQvNTQyMC8xNjM0LmF0b20iO31zOjg6ImZyYWdtZW50IjtzOjA6IiI7fQ== [7]: #xref-ref-2-1 View reference 2 in text