title: HINT1 protein: a new therapeutic target to enhance opioid antinociception and block mechanical allodynia.
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.
authors.affiliation: Neuropharmacology, Instituto Cajal, Consejo Superior de Investigaciones Científicas (CSIC), Avda Dr. Arce 37, 28002 Madrid, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Garzón
authors.forename: Raquel
authors.initials: R
authors.lastname: Herrero-Labrador
authors.forename: María
authors.initials: M
authors.lastname: Rodríguez-Muñoz
authors.forename: Rachit
authors.initials: R
authors.lastname: Shah
authors.forename: Ana
authors.initials: A
authors.lastname: Vicente-Sánchez
authors.forename: Carston R
authors.initials: CR
authors.lastname: Wagner
authors.forename: Pilar
authors.initials: P
authors.lastname: Sánchez-Blázquez
mesh_terms: D000701:Analgesics, Opioid / Q000627:therapeutic use*; D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D004195:Disease Models, Animal; D004361:Drug Tolerance; D005106:Exploratory Behavior / Q000187:drug effects; D006930:Hyperalgesia / Q000188:drug therapy* / Q000209:etiology; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009020:Morphine / Q000627:therapeutic use*; D009043:Motor Activity / Q000187:drug effects; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects; D059348:Peripheral Nerve Injuries / Q000150:complications; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics; D013550:Swimming / Q000523:psychology
chemical_list: D000701:Analgesics, Opioid; C489275:Hint1 protein, mouse; C409466:NR1 NMDA receptor; D009419:Nerve Tissue Proteins; D016194:Receptors, N-Methyl-D-Aspartate; D009020:Morphine