Antihyperalgesic effects of infection with a preproenkephalin-encoding herpes virus

Abstract

To test the utility of gene therapeutic approaches for the treatment of pain, a recombinant herpes simplex virus, type 1, has been engineered to contain the cDNA for an opioid peptide precursor, human preproenkephalin, under control of the human cytomegalovirus promoter. This virus and a similar recombinant containing the Escherichia coli lacZ gene were applied to the abraded skin of the dorsal hindpaw of mice. After infection, the presence of beta-galactosidase in neuronal cell bodies of the relevant spinal ganglia (lacZ-containing virus) and of human proenkephalin (preproenkephalin-encoding virus) in the central terminals of these neurons indicated appropriate gene delivery and expression. Baseline foot withdrawal responses to noxious radiant heat mediated by Adelta and C fibers were similar in animals infected with proenkephalin-encoding and beta-galactosidase-encoding viruses. Sensitization of the foot withdrawal response after application of capsaicin (C fibers) or dimethyl sulfoxide (Adelta fibers) observed in control animals was reduced or eliminated in animals infected with the proenkephalin-encoding virus for at least 7 weeks postinfection. Hence, preproenkephalin cDNA delivery selectively blocked hyperalgesia without disrupting baseline sensory neurotransmission. This blockade of sensitization was reversed by administration of the opioid antagonist naloxone, apparently acting in the spinal cord. The results demonstrate that the function of sensory neurons can be selectively altered by viral delivery of a transgene. Because hyperalgesic mechanisms may be important in establishing and maintaining neuropathic and other chronic pain states, this approach may be useful for treatment of chronic pain and hyperalgesia in humans.

Herpes virus-based recombinant herpes vectors: gene therapy for pain and molecular tool for pain science

“…Thus, we tried a similar experiment, except that this time we tried pretreating the skin with capsaicinthe component of hot peppers that make them hot-to sensitize the nociceptors innervating the epidermis to heat stimulation. 1 Repeating the experiment, we found that the vector treatment produced a robust antihyperalgesia, reversing the sensitizing effects of capsaicin. These effects held up for at least 7 weeks after infection.…”

Gene therapy for pancreatitis pain

“…20,21 Equivalent findings for reduction of pain-related behaviors, tissue damage and decreased inflammation with use of similar HSV preproenkephalin overexpression vectors are reported for cutaneous and knee joint pain models. 20,22,53,54 Released enkephalins have been measured in the spinal cord and skin using the same HSV-preproenkephalin vector injected cutaneously in rats and monkeys. 26,54 It is known that enkephalin directly inhibits neurotransmitter release, including substance P, from presynaptic nerve terminals in both the central and peripheral nervous systems, 55 through a calcium channel blocking action.…”

Inflammation et douleur : thérapie génique expérimentale

“…Surexpression du gène de la proenképhaline A Une stratégie différente a été utilisée par deux autres groupes [6,7] pour surexprimer la pEnkA dans les neu-…”

“…Ces vecteurs permettent l'introduction du transgène dans les corps cellulaires des neurones sensoriels à la suite d'une infection périphérique. Chez des souris dont les neurones sensoriels ont été préalablement sensibilisés par des agents chimiques, mimant les conditions rencontrées dans les douleurs inflammatoires prolongées, la surexpression de la pEnkA humaine (sous contrôle du promoteur CMV) dans ces neurones atténue l'hyperalgésie consécutive à l'inflammation [6]. La même approche a montré un effet antinociceptif dans des modèles expéri-mentaux de douleur de type inflammatoire ou neuropa-…”