Nasal application of HSV encoding human preproenkephalin blocks craniofacial pain in a rat model of traumatic brain injury.

According to Centers for Disease Control and Prevention, each year, an estimated 1.7 million Americans sustain a traumatic brain injury (TBI), which frequently leads to chronic craniofacial pain. In this study we examine a gene therapy approach to the treatment of post-TBI craniofacial neuropathic pain using nasal application of a herpes simplex virus (HSV)-based vector expressing human proenkephalin (SHPE) to target the trigeminal ganglia. Mild TBI was induced in rats by the use of a modified fluid percussion model. Two days after mild TBI, following the development of facial mechanical allodynia, animals received either an intranasal application of vehicle or recombinant HSV encoding human preproenkephalin or lacZ reporter gene encoding control vector (SHZ.1). Compared with baseline response thresholds, mild TBI in SHZ.1 or vehicle-treated animals induced a robust craniofacial allodynia lasting at least 45 days. On the other hand, nasal SHPE application 2 days post-TBI attenuated facial allodynia, reaching significance by day 4-7 and maintaining this effect throughout the duration of the experiment. Immunohistochemical examination revealed strong expression of human proenkephalin in trigeminal ganglia of SHPE, but not SHZ.1-treated rats. This study demonstrates that intranasal administration of HSV-based gene vectors may be a viable, non-invasive means of treating chronic craniofacial pain, including post-TBI pain.

Gene therapy for trigeminal pain in mice.

The aim of this study was to test the efficacy of a single direct injection of viral vector encoding for encephalin to induce a widespread expression of the transgene and potential analgesic effect in trigeminal behavioral pain models in mice. After direct injection of herpes simplex virus type 1 based vectors encoding for human preproenkephalin (SHPE) or the lacZ reporter gene (SHZ.1, control virus) into the trigeminal ganglia in mice, we performed an orofacial formalin test and assessed the cumulative nociceptive behavior at different time points after injection of the viral vectors. We observed an analgesic effect on nociceptive behavior that lasted up to 8 weeks after a single injection of SHPE into the trigeminal ganglia. Control virus-injected animals showed nociceptive behavior similar to naive mice. The analgesic effect of SHPE injection was reversed/attenuated by subcutaneous naloxone injections, a µ-opioid receptor antagonist. SHPE-injected mice also showed normalization in withdrawal latencies upon thermal noxious stimulation of inflamed ears after subdermal complete Freund's adjuvant injection, indicating widespread expression of the transgene. Quantitative immunohistochemistry of trigeminal ganglia showed expression of human preproenkephalin after SHPE injection. Direct injection of viral vectors proved to be useful for exploring the distinct pathophysiology of the trigeminal system and could also be an interesting addition to the pain therapists' armamentarium.