Adeno-associated virus-mediated gene transfer of arginine decarboxylase to the central nervous system prevents opioid analgesic tolerance

Caroline C. Churchill, Cristina D. Peterson, Kelley F. Kitto, Kelsey R. Pflepsen, Lalitha R. Belur, R. Scott McIvor, Lucy Vulchanova, George L. Wilcox, Carolyn A. Fairbanks

Research output: Contribution to journalArticlepeer-review

Abstract

Agmatine, a decarboxylated form of L-arginine, prevents opioid analgesic tolerance, dependence, and self-administration when given by both central and systemic routes of administration. Endogenous agmatine has been previously detected in the central nervous system. The presence of a biochemical pathway for agmatine synthesis offers the opportunity for site-specific overexpression of the presumptive synthetic enzyme for local therapeutic effects. In the present study, we evaluated the development of opioid analgesic tolerance in ICR-CD1 mice pre-treated with either vehicle control or intrathecally delivered adeno-associated viral vectors (AAV) carrying the gene for human arginine decarboxylase (hADC). Vehicle-treated or AAV-hADC-treated mice were each further divided into two groups which received repeated delivery over three days of either saline or systemically-delivered morphine intended to induce opioid analgesic tolerance. Morphine analgesic dose-response curves were constructed in all subjects on day four using the warm water tail flick assay as the dependent measure. We observed that pre-treatment with AAV-hADC prevented the development of analgesic tolerance to morphine. Peripheral and central nervous system tissues were collected and analyzed for presence of hADC mRNA. In a similar experiment, AAV-hADC pre-treatment prevented the development of analgesic tolerance to a high dose of the opioid neuropeptide endomorphin-2. Intrathecal delivery of anti-agmatine IgG (but not normal IgG) reversed the inhibition of endomorphin-2 analgesic tolerance in AAV-hADC-treated mice. To summarize, we report here the effects of AAV-mediated gene transfer of human ADC (hADC) in models of opioid-induced analgesic tolerance. This study suggests that gene therapy may contribute to reducing opioid analgesic tolerance.

Original languageEnglish (US)
Article number1269017
JournalFrontiers in Pain Research
Volume4
DOIs
StatePublished - 2023

Bibliographical note

Publisher Copyright:
2024 Churchill, Peterson, Kitto, Pflepsen, Belur, McIvor, Vulchanova, Wilcox and Fairbanks.

Keywords

  • AAV5
  • AAV9
  • NMDA receptor antagonism
  • agmatine
  • human arginine decarboxylase
  • intrathecal
  • opioid tolerance

PubMed: MeSH publication types

  • Journal Article

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