Peripheral non-viral MIDGE vector-driven delivery of beta-endorphin in inflammatory pain.
BACKGROUND
Leukocytes infiltrating inflamed tissue produce and release opioid peptides such as beta-endorphin, which activate opioid receptors on peripheral terminals of sensory nerves resulting in analgesia. Gene therapy is an attractive strategy to enhance continuous production of endogenous opioids. However, classical viral and plasmid vectors for gene delivery are hampered by immunogenicity, recombination, oncogene activation, anti-bacterial antibody production or changes in physiological gene expression. Non-viral, non-plasmid minimalistic, immunologically defined gene expression (MIDGE) vectors may overcome these problems as they carry only elements needed for gene transfer. Here, we investigated the effects of a nuclear localization sequence (NLS)-coupled MIDGE encoding the beta-endorphin precursor proopiomelanocortin (POMC) on complete Freund's adjuvant-induced inflammatory pain in rats.


RESULTS
POMC-MIDGE-NLS injected into inflamed paws appeared to be taken up by leukocytes resulting in higher concentrations of beta-endorphin in these cells. POMC-MIDGE-NLS treatment reversed enhanced mechanical sensitivity compared with control MIDGE-NLS. However, both effects were moderate, not always statistically significant or directly correlated with each other. Also, the anti-hyperalgesic actions could not be increased by enhancing beta-endorphin secretion or by modifying POMC-MIDGE-NLS to code for multiple copies of beta-endorphin.


CONCLUSIONS
Although MIDGE vectors circumvent side-effects associated with classical viral and plasmid vectors, the current POMC-MIDGE-NLS did not result in reliable analgesic effectiveness in our pain model. This was possibly associated with insufficient and variable efficacy in transfection and/or beta-endorphin production. Our data point at the importance of the reproducibility of gene therapy strategies for the control of chronic pain.
Machelska
Halina
H
Klinik für Anaesthesiologie und operative Intensivmedizin, Freie Universität Berlin, Medizinische Fakultät Charité-Campus Benjamin Franklin, Krahmerstrasse 6, D-12207 Berlin, Germany. halina.machelska@charite.de
Schroff
Matthias
M
Oswald
Detlef
D
Binder
Waltraud
W
Sitte
Nicolle
N
Mousa
Shaaban A
SA
Rittner
Heike L
HL
Brack
Alexander
A
Labuz
Dominika
D
Busch
Melanie
M
Wittig
Burghardt
B
Schäfer
Michael
M
Stein
Christoph
C
D000818:Animals; D005434:Flow Cytometry; D005822:Genetic Vectors; D007150:Immunohistochemistry; D007249:Inflammation / Q000628:therapy; D008297:Male; D051379:Mice; D008954:Models, Biological; D059408:Pain Management; D011333:Pro-Opiomelanocortin / Q000235:genetics; D011863:Radioimmunoassay; D051381:Rats; D017208:Rats, Wistar; D001615:beta-Endorphin / Q000235:genetics / Q000378:metabolism*
D001615:beta-Endorphin; D011333:Pro-Opiomelanocortin