HINT1 protein: A new therapeutic target to enhance opioid antinociception and block mechanical allodynia

Javier Garzón, Raquel Herrero-Labrador, María Rodríguez-Muñoz, Rachit Shah, Ana Vicente-Sánchez, Carston R. Wagner, Pilar Sánchez-Blázquez

Research output: Contribution to journalArticle

26 Scopus citations

Abstract

In the nervous system, the glutamate N-methyl-D-aspartate receptor (NMDAR) restricts the activity of the mu-opioid receptor (MOR). Both receptors are present in midbrain periaqueductal grey (PAG) neurons, an area that plays a central role in the supraspinal antinociceptive effects of opioids. The cross-talk that occurs between these receptors is sustained by the MOR-associated histidine triad nucleotide binding protein 1 (HINT1), which displays nucleoside phosphoramidase and acyl-AMP hydrolase activity. Here we report that the inhibitor of HINT1 enzymatic activity guanosine-5′-tryptamine carbamate (TpGc) significantly enhanced morphine antinociception while preventing the development of tolerance. At the molecular level, TpGc reduced the capacity of MORs to recruit NMDAR activity to negatively regulate opioid signaling. In mice suffering from chronic constriction injury concurrent with increased NMDAR activity, a single intracerebroventricular administration of TpGc attenuated NMDAR function and alleviated mechanical allodynia for several days. These data suggest a potential therapeutic role for HINT1 inhibitors in the clinical management of acute and neuropathic pain.

Original languageEnglish (US)
Pages (from-to)412-423
Number of pages12
JournalNeuropharmacology
Volume89
DOIs
StatePublished - Feb 2015

Keywords

  • Antinociception
  • Glutamate N-methyl-D-aspartate receptor
  • Guanosine-5′-tryptamine carbamate
  • Histidine triad nucleotide binding protein 1
  • Mu-opioid receptor
  • PKCγ
  • Receptor desensitization

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    Garzón, J., Herrero-Labrador, R., Rodríguez-Muñoz, M., Shah, R., Vicente-Sánchez, A., Wagner, C. R., & Sánchez-Blázquez, P. (2015). HINT1 protein: A new therapeutic target to enhance opioid antinociception and block mechanical allodynia. Neuropharmacology, 89, 412-423. https://doi.org/10.1016/j.neuropharm.2014.10.022