Agmatine preferentially antagonizes GluN2B-containing N-methyl-D-aspartate receptors in spinal cord

Jonathan J. Waataja, Cristina D. Peterson, Harsha Verma, Cory J. Goracke-Postle, Philippe Séguéla, Eric Delpire, George L. Wilcox, Carolyn A. Fairbanks

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

The role of the N-methyl- D -aspartate receptor (NMDAr) as a contributor to maladaptive neuroplasticity underlying the maintenance of chronic pain is well established. Agmatine, an NMDAr antagonist, has been shown to reverse tactile hypersensitivity in rodent models of neuropathic pain while lacking the side effects characteristic of global NMDAr antagonism, including sedation and motor impairment, indicating a likely subunit specificity of agmatine’s NMDAr inhibition. The present study assessed whether agmatine inhibits subunit-specific NMDAr-mediated current in the dorsal horn of mouse spinal cord slices. We isolated NMDAr-mediated excitatory postsynaptic currents (EPSCs) in small lamina II dorsal horn neurons evoked by optogenetic stimulation of Na v 1.8-containing nociceptive afferents. We determined that agmatine abbreviated the amplitude, duration, and decay constant of NMDAr-mediated EPSCs similarly to the application of the GluN2B antagonist ifenprodil. In addition, we developed a site-specific knockdown of the GluN2B subunit of the NMDAr. We assessed whether agmatine and ifenprodil were able to inhibit NMDAr-mediated current in the spinal cord dorsal horn of mice lacking the GluN2B subunit of the NMDAr by analysis of electrically evoked EPSCs. In control mouse spinal cord, agmatine and ifenprodil both inhibited amplitude and accelerated the decay kinetics. However, agmatine and ifenprodil failed to attenuate the decay kinetics of NMDAr-mediated EPSCs in the GluN2B-knockdown mouse spinal cord. The present study indicates that agmatine preferentially antagonizes GluN2B-containing NMDArs in mouse dorsal horn neurons. NEW & NOTEWORTHY Our study is the first to report that agmatine preferentially antagonizes the GluN2B receptor subunit of the N-methyl- D -aspartate (NMDA) receptor in spinal cord. The preferential targeting of GluN2B receptor is consistent with the pharmacological profile of agmatine in that it reduces chronic pain without the motor side effects commonly seen with non-subunit-selective NMDA receptor antagonists.

Original languageEnglish (US)
Pages (from-to)662-671
Number of pages10
JournalJournal of neurophysiology
Volume121
Issue number2
DOIs
StatePublished - Feb 2019

Bibliographical note

Funding Information:
This work was supported by National Institutes of Health (NIH) Grant R01 DA035931 (to C. A. Fairbanks), and NIH Training Grant T32 DA007097 supported both C. D. Peterson and J. J. Waataja. The Gene-Targeted Mouse Core of the INIAstress consortium is supported by NIH Grant AA013514 (to E. Delpire).

Publisher Copyright:
© 2019 the American Physiological Society.

Copyright:
Copyright 2019 Elsevier B.V., All rights reserved.

Keywords

  • -arginine
  • Agmatine
  • Arginine decarboxylase
  • Glutamate
  • Neuroplasticity
  • Polyamine

Fingerprint

Dive into the research topics of 'Agmatine preferentially antagonizes GluN2B-containing N-methyl-D-aspartate receptors in spinal cord'. Together they form a unique fingerprint.

Cite this