Nerve injury leads to many changes in the peripheral and central nervous system leading to altered somatic sensation. These sensory changes, including pain, are particularly resistant to treatment and the currently available drugs do not offer adequate relief in addition to having many unwanted side effects. Gene therapy offers a new and promising method of attacking pain because it can target specific areas of the nervous system and it has long-lived effects. We use a well-established method for transferring gene vector into sensory neurons that could eventually be used clinically. The gene we will transfer codes for the enzyme responsible for the synthesis of GABA, the main inhibitory neurotransmitter of the nervous system. Treatment with drugs that increase GABA in the nervous system is known to produce relief in a number of pain conditions. We use gene transfer to increase GABA in neurons of the trigeminal ganglion that supply the sensory innervations of the face and find that this results in analgesia in rats with nerve injury induced facial pain. This is an encouraging indication a similar gene transfer strategy would provide pain relief to the many patients with chronic intractable facial pain. Before contemplating a human trial, however, some key questions concerning the mechanism underlying the effect of the transferred genes need to be answered and are the subject of the present experimental protocol. Firstly, we will identify the site of action of the GABA synthesized by the transected genes. Secondly, we will see if inserting two versus only one of the two genes coding for the GABA producing enzyme results in more pain relief. Thirdly, we will determine if transferring the gene to different populations of sensory neurons can modify different components of pain sensation. Finally, we will determine if GABA therapy given before the nerve injury is more, or less, efficacious than therapy give after the injury in preventing or reversing some of the key changes linked to pain sensation occurring in the nervous system. ? Oral, facial, and head pain from trigeminal nerve dysfunction is a common clinical problem and one of the most challenging to treat. Gene therapy is a better method for pain control because it avoids many of the drawbacks of drugs or ablative treatments such as surgery or radiation. Our project is a pre-clinical study of the analgesic effects of correcting trigeminal nerve dysfunction by adding a gene that codes for GABA, a natural neurotransmitter to trigeminal nerve neurons. ? ? ?
