Overexpression of μ-opioid receptors in peripheral afferents, but not in combination with enkephalin, decreases neuropathic pain behavior and enhances opioid analgesia in mouse

Background: The current study used recombinant herpes simplex virus type I to increase expression of μ-opiate receptors and the opioid ligand preproenkephalin in peripheral nerve fibers in a mouse model of neuropathic pain. It was predicted that viral vector delivery of a combination of genes encoding the μ-opioid receptor and preproenkephalin would attenuate neuropathic pain and enhance opioid analgesia. The behavioral effects would be paralleled by changes in response properties of primary afferent neurons. Methods: Recombinant herpes simplex virus type 1 containing cDNA sequences of the μ-opioid receptor, human preproenkephalin, a combination, or Escherichia coli lacZ gene marker (as a control) was used to investigate the role of peripheral opioids in neuropathic pain behaviors. Results: Inoculation with the μ-opioid receptor viral vector (n = 13) reversed mechanical allodynia and thermal hyperalgesia and produced leftward shifts in loperamide (ED50 = 0.6 ± 0.2 mg/kg vs. ED50 = 0.9 ± 0.2 mg/kg for control group, n = 8, means ± SD) and morphine dose-response curves (ED50 = 0.3 ± 0.5 mg/kg vs. ED50 = 1.1 ± 0.1 mg/kg for control group). In μ-opioid receptor viral vector inoculated C-fibers, heat-evoked responses (n = 12) and ongoing spontaneous activity (n = 18) were decreased after morphine application. Inoculation with both μ-opioid receptor and preproenkephalin viral vectors did not alter mechanical and thermal responses. Conclusions: Increasing primary afferent expression of opioid receptors can decrease neuropathic pain-associated behaviors and increase systemic opioid analgesia through inhibition of peripheral afferent fiber activity.