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

doi:10.3389/fpain.2023.1269017

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

Front Pain Res (Lausanne). 2024 Feb 9:4:1269017. doi: 10.3389/fpain.2023.1269017. eCollection 2023.

Authors

Caroline C Churchill¹, Cristina D Peterson^{1

2

3}, Kelley F Kitto², Kelsey R Pflepsen³, Lalitha R Belur⁴, R Scott McIvor⁴, Lucy Vulchanova², George L Wilcox^{2

5

6}, Carolyn A Fairbanks^{2

3

5}

Affiliations

¹ Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, MN, United States.
² Department of Neuroscience, University of Minnesota, Minneapolis, MN, United States.
³ Department of Pharmaceutics, University of Minnesota, Minneapolis, MN, United States.
⁴ Department of Genetics Cell Biology and Development, University of Minnesota, Minneapolis, MN, United States.
⁵ Department of Pharmacology, University of Minnesota, Minneapolis, MN, United States.
⁶ Department of Dermatology, University of Minnesota, Minneapolis, MN, United States.

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.

Keywords: AAV5; AAV9; NMDA receptor antagonism; agmatine; human arginine decarboxylase; intrathecal; opioid tolerance.

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article.