Long-term reversal of chronic pain behavior in rodents through elevation of spinal agmatine

Cristina D Peterson, Jonathan J. Waataja, Kelley F. Kitto, Samuel J Erb, Harsha Verma, Daniel Schuster, Caroline C Churchill, Maureen S. Riedl, Lalitha R. Belur, Daniel A. Wolf, R. Scott McIvor, Lucy Vulchanova, George L. Wilcox, Carolyn A. Fairbanks

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Chronic pain remains a significant burden worldwide, and treatments are often limited by safety or efficacy. The decarboxylated form of L-arginine, agmatine, antagonizes N-methyl-D-aspartate receptors, inhibits nitric oxide synthase, and reverses behavioral neuroplasticity. We hypothesized that expressing the proposed synthetic enzyme for agmatine in the sensory pathway could reduce chronic pain without motor deficits. Intrathecal delivery of an adeno-associated viral (AAV) vector carrying the gene for arginine decarboxylase (ADC) prevented the development of chronic neuropathic pain as induced by spared nerve injury in mice and rats and persistently reversed established hypersensitivity 266 days post-injury. Spinal long-term potentiation was inhibited by both exogenous agmatine and AAV-human ADC (hADC) vector pre-treatment but was enhanced in rats treated with anti-agmatine immunoneutralizing antibodies. These data suggest that endogenous agmatine modulates the neuroplasticity associated with chronic pain. Development of approaches to access this inhibitory control of neuroplasticity associated with chronic pain may yield important non-opioid pain-relieving options.

Original languageEnglish (US)
Pages (from-to)1123-1135
Number of pages13
JournalMolecular Therapy
Volume31
Issue number4
DOIs
StatePublished - Apr 5 2023

Bibliographical note

Funding Information:
These studies were supported by contributions from the following sources: the National Institute on Drug Abuse ( R01DA025164 to C.A.F.; K01DA017236 to L.V.; R01DA015238 to G.L.W), the University of Minnesota Academic Health Center, and the University of Minnesota College of Pharmacy Engebretson Grant Award (to C.A.F.). A Neurosensory and Rehabilitation Research Award from the Congressionally Medically Directed Research Program of the Department of Defense ( W81XWH-15-1-0494 ) and training grant fellowships from the National Institute on Drug Abuse supported several authors (T32A07234 to S.E.; T32DA0070970 to C.D.P., J.J.W., and C.C.C.). An individual National Research Service Award (NRSA) from the National Institute of Neurological Disorders and Stroke ( F31NS063634 ) supported D.J.S. 3M Fellowships supported D.J.S. and C.C.C. We acknowledge Oanh Nguyen for project administration and lab management and Andrea Karlen for technical assistance with AAV preparation.

Funding Information:
These studies were supported by contributions from the following sources: the National Institute on Drug Abuse (R01DA025164 to C.A.F.; K01DA017236 to L.V.; R01DA015238 to G.L.W), the University of Minnesota Academic Health Center, and the University of Minnesota College of Pharmacy Engebretson Grant Award (to C.A.F.). A Neurosensory and Rehabilitation Research Award from the Congressionally Medically Directed Research Program of the Department of Defense (W81XWH-15-1-0494) and training grant fellowships from the National Institute on Drug Abuse supported several authors (T32A07234 to S.E.; T32DA0070970 to C.D.P. J.J.W. and C.C.C.). An individual National Research Service Award (NRSA) from the National Institute of Neurological Disorders and Stroke (F31NS063634) supported D.J.S. 3M Fellowships supported D.J.S. and C.C.C. We acknowledge Oanh Nguyen for project administration and lab management and Andrea Karlen for technical assistance with AAV preparation. Conceptualization: C.D.P. L.V. G.L.W. and C.A.F.; funding acquisition: L.V. G.L.W. and C.A.F.; investigation: C.D.P. J.J.W. K.F.K. S.E. H.V. D.J.S. C.C.C. M.S.R. L.R.B. L.V. and C.A.F.; electrophysiological experiments: J.J.W.; bioanalytical analysis: S.E. and C.C.C.; molecular analysis: H.V.; project administration: C.D.P. and C.A.F.; supervision: C.D.P. R.S.M. L.V. G.L.W. and C.A.F.; writing – original draft: C.D.P. J.J.W. S.E. H.V. L.R.B. R.S.M. L.V. G.L.W. and C.A.F.; writing – review and editing: C.D.P. J.J.W. D.J.S. C.C.C. M.S.R. L.R.B. L.V. G.L.W. and C.A.F. The authors declare no competing interests.

Publisher Copyright:
© 2023 The American Society of Gene and Cell Therapy

Keywords

  • AAV gene therapy
  • NMDA receptor
  • agmatine
  • analgesia
  • arginine decarboxylase
  • chronic pain
  • neuropathic pain
  • neuroplasticity
  • spinal electrophysiology
  • spinal long-term potentiation

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