| Abstract
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Chronic neuropathic pain is a disabling condition which is often refractory to current analgesic therapies, specifically opioid analgesia. This study tested the hypothesis that virally mediated expression of mu opioid receptor (MOR), delta opioid receptor (DOR), and their endogenous ligand, enkephalin (Enk), would attenuate neuropathic pain-associated behaviors and enhances opioid analgesia. We first investigated basal nociception, capsaicin-induced hyperalgesia, and opioid analgesia after topical infection with a recombinant herpes simplex virus type 1 (HSV-1) containing cDNA sequences for mu-opioid receptor (SGMOR), human preproenkephalin (KPE), a mix of SGMOR and KPE, or E. coli lacZ gene marker (SGZ), which served as a control vector. In comparison to the control group, SGMOR, KPE, and SGMOR+KPE groups exhibited higher mechanical withdrawal thresholds and higher thermal withdrawal latencies. In response to intraplantar capsaicin SGMOR, KPE, and SGMOR+ KPE groups had lower spontaneous nociceptive behaviors, shorter duration of capsaicin-induced hyperalgesia, and reduced c-fos immunoreactivity in the dorsal horn of spinal cord. In addition, SGMOR, KPE, and SGMOR+ KPE groups exhibited a leftward shift in the dose-response curve of loperamide, a peripheral opioid agonist, compared to the control group. We then employed these viral vectors to study HSV-mediated expression of MOR and Enk in the primary afferent neurons in nerve-injured mice at the level of skin, DRG, and spinal cord. We also examined the attenuation of mechanical allodynia and thermal hyperalgesia and the shift in opioid analgesia after viral administration. In mice infected with the SGMOR and KPE viruses, mechanical allodynia returned to baseline by day 9 and exceeded baseline by day 16 post-infection. In contrast, mice infected with the combined SGMOR + KPE viruses did not change mechanical allodynia. Thermal hyperalgesia also resolved quicker in SGMOR infected mice and exceeded baseline. In contrast, KPE infection had no effect on thermal hyperalgesia. Mice infected with the combined SGMOR+KPE had a persistent hyperalgesia which lasted the entire study. A leftward shift in loperamide, a peripherally opioid agonist, and morphine, a centrally opioid agonist, dose-response curve was observed following SGMOR infection. A smaller leftward shift in the morphine, but not loperamide dose-response curve was observed in KPE infected mice. Interestingly, a rightward shift in loperamide and morphine dose-response curve was observed in mice infected with the combined SGMOR + KPE viruses. Finally, we employed viral vectors encoding delta-opioid receptor in the sense orientation (NPDOR), delta-opioid receptor in the anti-sense orientation (NPADOR) or E. coli LacZ gene markers (K/NPZ+SGZ) as control vectors in nerve-injured mice. Mice were infected with SGMOR, NPDOR, NPADOR, KPE, combined SGMOR/NPDOR + KPE, combined SGMOR+NPADOR or control viruses via subcutaneous injection in the ipsilateral plantar hindpaw. In mice infected with the NPADOR virus and the combined SGMOR+NPADOR viruses, mechanical allodynia returned to baseline by day 3 post viral administration in the NPADOR infected mice and by day 5 post viral administration in the combined SGMOR+ NPADOR infected mice. In addition, in SGMOR+NPADOR infected mice, mechanical allodynia exceeded baseline values by day 9 post-infection. In contrast, mice NPDOR and the combined NPDOR+KPE viruses infected mice had a persistent mechanical allodynia lasted for duration of the study. Thermal hyperalgesia also resolved fast in NPADOR and the combined NPADOR+SGMOR infected mice. In contrast, NPDOR had no effect on thermal hyperalgesia. Mice infected with the combined NPDOR+KPE had a persistent hyperalgesia which lasted the entire study. A leftward shift in loperamide, a peripherally opioid agonist, and morphine, a centrally opioid agonist, dose-response curve was observed following NPADOR and the combined NPADOR+SGMOR infection. Small rightward shift in morphine, but not loperamide, does-response curve was observed in NPDOR infected mice. Interestingly, a rightward shift in loperamide and morphine dose-response curve was observed in mice infected with the combined NPDOR + KPE viruses. These results demonstrate that neuropathic pain pathology and opioid analgesia involve intricate interaction between the components of the endogenous opioid system. Hence, this approach may serve as the basis for a more effective treatment for chronic pain.
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