Peripheral non-viral MIDGE vector-driven delivery of β-endorphin in inflammatory pain

POMC-MIDGE-NLS injected into inflamed paws appeared to be taken up by leukocytes resulting in higher concentrations of β-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 β-endorphin secretion or by modifying POMC-MIDGE-NLS to code for multiple copies of β-endorphin.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 β-endorphin production. Our data point at the importance of the reproducibility of gene therapy strategies for the control of chronic pain.Exogenous opioids (e.g. morphine), and endogenous opioid peptides, such as β-endorphin (END) and enkephalins, are powerful analgesics in animals and humans [1-3]. Compared to conventional exogenous agonists, endogenous opioids have several advantages. These include reduced probabilities of receptor downregulation and of paradoxical excitatory effects due to high non-physiological exogenous agonist concentrations at the receptor [4]. Gene therapy is an attractive strategy to enhance continuous production of endogenous opioids. The most often used vectors are recombinant viruses. Several laboratories have employed herpes simplex virus (HSV) encoding preproenkephalin (PPENK) to increase enkephalin production. Transfection of the spinal cord, trigeminal or dorsal root ganglia (DRG) with such vectors resulted in the attenuation of nociceptive behaviors in animal models of acute and pathological pain [5-13]. Similar effects were found after hind paw inoculation with HSV encoding endomorphin-2 [14] or spinal application of adenoviral a