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

ABSTRACT: 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.

SUBMITTER: Klein AH

PROVIDER: S-EPMC5904001 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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

Klein Amanda H AH Mohammad Husam K HK Ali Rabiah R Peper Brad B Wilson Steven P SP Raja Srinivasa N SN Ringkamp Matthias M Sweitzer Sarah S

Anesthesiology 20180501 5

<h4>Background</h4>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 prim ...[more]

PMID: 29334500

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Project description:Background: Functional deletion of the Scn9a (sodium voltage-gated channel alpha subunit 9) gene encoding sodium channel Nav1.7 makes humans and mice pain-free. Opioid signalling contributes to this analgesic state. We have used pharmacological and genetic approaches to identify the opioid receptors involved in this form of analgesia. We also examined the regulation of proenkephalin expression by the transcription factor Nfat5 that binds upstream of the Penk gene. Methods: We used specific µ-, δ- and κ-opioid receptor antagonists alone or in combination to examine which opioid receptors were necessary for Nav1.7 loss-associated analgesia in mouse behavioural assays of thermal pain. We also used µ- and δ-opioid receptor null mutant mice alone and in combination in behavioural assays to examine the role of these receptors in Nav1.7 knockouts pain free phenotype. Finally, we examined the levels of Penk mRNA in Nfat5-null mutant mice, as this transcription factor binds to consensus sequences upstream of the Penk gene. Results: The pharmacological block or deletion of both µ- and δ-opioid receptors was required to abolish Nav1.7-null opioid-related analgesia. κ-opioid receptor antagonists were without effect. Enkephalins encoded by the Penk gene are upregulated in Nav1.7 nulls. Deleting Nfat5, a transcription factor with binding motifs upstream of Penk, induces the same level of enkephalin mRNA expression as found in Nav1 .7 nulls, but without consequent analgesia. These data confirm that a combination of events linked to Scn9a gene loss is required for analgesia. Higher levels of endogenous enkephalins, potentiated opioid receptors, diminished electrical excitability and loss of neurotransmitter release together contribute to the analgesic phenotype found in Nav1.7-null mouse and human mutants. Conclusions: These observations help explain the failure of Nav1.7 channel blockers alone to produce analgesia and suggest new routes for analgesic drug development.

Dataset Information

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

Publications

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

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