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

• Published in: Neuropharmacology 2015-02, Vol.89, p.412-423
• Main Authors: Garzón, Javier, Herrero-Labrador, Raquel, Rodríguez-Muñoz, María, Shah, Rachit, Vicente-Sánchez, Ana, Wagner, Carston R., Sánchez-Blázquez, Pilar
• Format: Article
• Language: English
• Subjects: Analgesics, Opioid - therapeutic use; Animals; Antinociception; Cells, Cultured; Cerebral Cortex - cytology; Disease Models, Animal; Drug Tolerance; Exploratory Behavior - drug effects; glutamate N-methyl-d-aspartate receptor; Guanosine-5′-tryptamine carbamate; Histidine triad nucleotide binding protein 1; Hyperalgesia - drug therapy; Hyperalgesia - etiology; In Vitro Techniques; Male; Mice; Mice, Transgenic; Morphine - therapeutic use; Motor Activity - drug effects; Mu-opioid receptor; Nerve Tissue Proteins - antagonists & inhibitors; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Neurons - drug effects; Peripheral Nerve Injuries - complications; PKCγ; Receptor desensitization; Receptors, N-Methyl-D-Aspartate - genetics; Swimming - psychology
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/j.neuropharm.2014.10.022

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. •The HINT1 protein engages NMDAR negative control on MOR signaling.•The HINT1 enzymatic inhibitor TpGc disconnects MOR effects from NMDAR control.•TpGc enhances morphine antinociception and reduces acute tolerance.•TpGc reduces allodynia in the CCI animal model of neuropathic pain.•A single icv injection of 20 nmol TpGc alleviates CCI-evoked allodynia for three days.