Gene therapy for chronic pain: How to manipulate and unravel pain control circuits from the brain?

Abstract

The increasing prevalence of chronic pain imposes to search for new therapeutic approaches. Despite the increase in basic and clinical pain research during the last decades, the available analgesic drugs remained considerably unchanged. Gene therapy emerged as an important tool in the pain fi eld. Studies in experimental pain models consisted on blockade of nociceptive transmission at the spinal cord by peripheral delivery of viral vectors (mainly replication-defective forms of herpes simplex virus type 1, HSV-1). Based on these results, clinical trials using gene therapy were successfully implemented in cancer patients with intractable pain. The studies at the spinal cord opened the possibility to use gene transfer to interfere in a specifi c and sustained manner with pain control areas of the brain. Our research group departed from detailed morphological and functional characterization of pain control circuits of the brainstem to develop strategies to manipulate those areas using HSV-1 vectors. First, we established the dynamics of migration of HSV-1 upon injection into a unique pain facilitatory area of the medulla oblongata (the dorsal reticular nucleus- DRt). At shorter postinjection timepoints, transduction occurred mainly at the DRt, whereas at longer times a selective migration was detected in DRt brain afferents. Since some of those afferents were noradrenergic and based on the role of noradrenaline in increasing pain facilitation from the DRt, we engineered an HSV-1 vector that contains the tyrosine hydroxylase (TH) promoter and the TH transgene in antisense orientation. This vector decreased neuropathic pain behaviors for about a month. Similar studies addressing other brain areas involved in descending pain modulation are necessary to fully ascertain the full potential of gene therapy for chronic pain control.