Transgene-mediated enkephalin release enhances the effect of morphine and evades tolerance to produce a sustained antiallodynic effect in neuropathic pain.
We examined the pharmacologic characteristics of herpes simplex virus (HSV) vector-mediated expression of proenkephalin in the dorsal root ganglion in a rodent model of neuropathic pain. We found that: (i). vector-mediated enkephalin produced an antiallodynic effect that was reversed by naloxone; (ii). vector-mediated enkephalin production in animals with spinal nerve ligation prevented the induction of c-fos expression in second order sensory neurons in the dorsal horn of spinal cord; (iii). the effect of vector-mediated enkephalin enhanced the effect of morphine, reducing the ED(50) of morphine 10-fold; (iv). animals did not develop tolerance to the continued production of vector-mediated enkephalin over a period of several weeks; and, (v). vector transduction continued to provide an analgesic effect despite the induction of tolerance to morphine. This is the first demonstration of gene transfer to provide an analgesic effect in neuropathic pain. The pharmacologic analysis demonstrates that transgene-mediated expression and local release of opioid peptides produce some effects that are distinct from peptide analogues delivered pharmacologically.
Hao
Shuanglin
S
Department of Neurology, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Mata
Marina
M
Goins
William
W
Glorioso
Joseph C
JC
Fink
David J
DJ
D000818:Animals; D019540:Area Under Curve; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D004745:Enkephalins / Q000235:genetics / Q000502:physiology*; D005727:Ganglia, Spinal / Q000378:metabolism; D005822:Genetic Vectors; D007150:Immunohistochemistry / Q000379:methods; D008026:Ligation / Q000379:methods; D008297:Male; D009020:Morphine / Q000627:therapeutic use*; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D016761:Oncogene Proteins v-fos / Q000378:metabolism; D010146:Pain / Q000188:drug therapy* / Q000503:physiopathology; D010147:Pain Measurement; D017288:Pain Threshold / Q000502:physiology; D011498:Protein Precursors; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D018139:Simplexvirus / Q000235:genetics; D013118:Spinal Cord Diseases / Q000473:pathology / Q000503:physiopathology; D013997:Time Factors; D019076:Transgenes
D004745:Enkephalins; D009292:Narcotic Antagonists; D016761:Oncogene Proteins v-fos; D011498:Protein Precursors; C029992:proenkephalin; D009270:Naloxone; D009020:Morphine