Efficacy of Herpes Simplex Virus Vector Encoding the Human Preproenkephalin Gene for Treatment of Facial Pain in Mice

Abstract

Aims To determine whether herpes simplex virus–based vectors can efficiently transduce mouse trigeminal ganglion (TG) neurons and attenuate preexisting nerve injury–induced whisker pad mechanical hypersensitivity in a trigeminal inflammatory compression (TIC) neuropathic pain model. Methods Tissue transduction efficiencies of replication-conditional and replication-defective vectors to mouse whisker pads after topical administration and subcutaneous injection were assessed using quantitative real-time PCR (qPCR). Tissue tropism and transgene expression were assessed using qPCR and reverse-transcriptase qPCR following topical application of the vectors. Whisker pad mechanical sensitivities of TIC-injured mice were determined using graduated von Frey fibers before and after application of human preproenkephalin expressing replication-conditional vector (KHPE). Data were analyzed using one-way analysis of variance (ANOVA) and post hoc tests. Results Transduction of target TGs was 8- to 50-fold greater after topical application than subcutaneous injection and ≥ 100-fold greater for replication-conditional than replication-defective vectors. Mean KHPE loads remained constant in TGs (4.5–9.8 × 104 copies/TG) over 3 weeks but were below quantifiable levels (10 copies/tissue) within 2 weeks of application in other nontarget cephalic tissues examined. Transgene expression in TGs was maximal during 2 weeks after topical application (100–200 cDNA copies/mL) and was below quantifiable levels (1 cDNA copy/mL) in all nontarget tissues. Topical KHPE administration reduced TIC-related mechanical hypersensitivity on whisker pads 4-fold (P < .05) for at least 1 week. Conclusion Topically administered KHPE produced a significant antinociceptive effect in the TIC mouse model of chronic facial neuropathic pain. This is the first report in which a gene therapeutic approach reduced trigeminal pain–related behaviors in an established pain state in mice.

Overexpression of µ-Opioid Receptors in Peripheral Afferents, but Not in Combination with Enkephalin, Decreases Neuropathic Pain Behavior and Enhances Opioid Analgesia in Mouse

“…Surprisingly, in this study, infection with hsvPPE did not reverse thermal hyperalgesia and had no effect on morphine analgesia in nerve injured mice. This is different from previous studies showing a reduction of neuropathic pain in rodent models of nerve injury 18,49 , and capsaicin induced pain 15 . It is noteworthy that our behavioral studies were conducted at least two weeks post intradermal injection of the virus and nerve injury, and experiments included female mice.…”

Diabetic neuropathic pain induced by streptozotocin alters the expression profile of non‑coding RNAs in the spinal cord of mice as determined by sequencing analysis

“…In the present study, numerous DE miRNAs were detected and miR-122 was the most notably upregulated miRNA. It was previously reported that miR-122 is involved in the regulation of neuropathic pain (30); however, whether miR-122 regulates DNP remains elusive and further studies are required to determine this. Although DE miRNAs in the spinal cord of mice with DNP were screened and the differential expression of certain miRNAs was confirmed in the present study, the underlying mechanisms of miRNAs in DNP are poorly understood.…”

Histone deacetylase inhibitors prevent persistent hypersensitivity in an orofacial neuropathic pain model

“…RNA was reverse transcribed and quantified by quantitative real-time PCR. 21 Sprr1a, Gal, Atf3, and GAPDH TaqMan gene expression assays were purchased from Life Technologies Corporation (Carlsbad, CA). Real-time PCR was performed on an ABI Prism 7700 Sequence Detection system (PE Applied Biosystems, Foster City, CA, USA) in a 20 µl reaction volume consisting of final concentrations of 1X TaqMan Universal PCR master mix (PE Applied Biosystems) and 1× respective gene expression assays using default conditions.…”