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.
Bibliographical noteFunding Information:
We would like to thank Gabriela de Alba and Carmelo Aguado for their excellent technical assistance. This research was supported by MSC ‘Plan de Drogas 2011–14’ and the Ministerio de Economía y Competividad (MINECO) , SAF 2012-34991 . The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors have no conflicts of interest. CRW also wish to thank the University of Minnesota Foundation for partial support of this research.
- Glutamate N-methyl-D-aspartate receptor
- Guanosine-5′-tryptamine carbamate
- Histidine triad nucleotide binding protein 1
- Mu-opioid receptor
- Receptor desensitization