Inhibition of HINT1 Modulates Spinal Nociception and NMDA Evoked Behavior in Mice

Rachit M. Shah, Cristina Peterson, Alexander Strom, Maxwell Dillenburg, Barry Finzel, Kelley F. Kitto, Carolyn Fairbanks, George Wilcox, Carston R. Wagner

Research output: Contribution to journalArticlepeer-review

10 Scopus citations


The interactions between the mu-opioid (MOR) and N-methyl-d-aspartate receptor (NMDAR) constitute an area of intense investigation because of their contributions to maladaptive neuroplasticity. Recent evidence suggests that their association requires the involvement of histidine triad nucleotide-binding protein (HINT1) with the enzyme's active site being critical in its regulatory role. Since it is known that spinal blockade of NMDA receptors prevents the development of opioid analgesic tolerance, we hypothesized that spinal inhibition of the HINT1 enzyme may similarly inhibit opioid tolerance. To address these questions, we evaluated novel HINT1 active-site inhibitors in two models of NMDAR and MOR interaction, namely, MOR inhibition of spinal NMDA activation and acute endomorphin-2 tolerance. These studies revealed that while the tryptamine carbamate of guanosine inhibitor, TrpGc, blocked both the development of opioid tolerance and the inhibitory effect of opioids on NMDA activation of the NMDA receptor, acyl-sulfamate analogues could only block the latter. Thermodynamic binding and X-ray crystallographic studies suggested that there are key differences between the bound HINT1-inhibitor surfaces that may be responsible for their differential ability to probe the ability of HINT1 to regulate cross talk between the mu-opioid receptor and NMDA receptor in the spinal cord.

Original languageEnglish (US)
Pages (from-to)4385-4393
Number of pages9
JournalACS Chemical Neuroscience
Issue number10
StatePublished - Oct 16 2019

Bibliographical note

Funding Information:
The studies were generously supported with Wallin Discovery Fund for Neuroscience at University of Minnesota. We also thankfully acknowledge funding from the University of Minnesota Endowment and Funding from the University of Minnesota Foundation. Use of the IMCA-CAT beamline 17-ID at the Advanced Photon Source was supported by the companies of the Industrial Macromolecular Crystallography Association through a contract with Hauptman– Woodward Medical Research Institute. This research used resources of the Advanced Photon Source, a U.S. Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under Contract No. DE-AC02-06CH11357.

Publisher Copyright:
Copyright © 2019 American Chemical Society.


  • Histidine triad nucleotide binding protein1 (HINT1)
  • N-methyl- d -aspartate receptors
  • mechanical allodynia
  • mu-opioid receptors
  • neuropathic pain
  • opioid analgesia


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