title: The histidine triad nucleotide-binding protein 1 supports mu-opioid receptor-glutamate NMDA receptor cross-regulation.
abstract: A series of pharmacological and physiological studies have demonstrated the functional cross-regulation between MOR and NMDAR. These receptors coexist at postsynaptic sites in midbrain periaqueductal grey (PAG) neurons, an area implicated in the analgesic effects of opioids like morphine. In this study, we found that the MOR-associated histidine triad nucleotide-binding protein 1 (HINT1) is essential for maintaining the connection between the NMDAR and MOR. Morphine-induced analgesic tolerance is prevented and even rescued by inhibiting PKC or by antagonizing NMDAR. However, in the absence of HINT1, the MOR becomes supersensitive to morphine before suffering a profound and lasting desensitization that is refractory to PKC inhibition or NMDAR antagonism. Thus, HINT1 emerges as a key protein that is critical for sustaining NMDAR-mediated regulation of MOR signaling strength. Thus, HINT1 deficiency may contribute to opioid-intractable pain syndromes by causing long-term MOR desensitization via mechanisms independent of NMDAR.
authors.affiliation: Centro de Investigación Biomédica en Red de Salud Mental, CIBERSAM, ISCIII, Avda Dr. Arce 37, 28002, Madrid, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Rodríguez-Muñoz
authors.forename: Pilar
authors.initials: P
authors.lastname: Sánchez-Blázquez
authors.forename: Ana
authors.initials: A
authors.lastname: Vicente-Sánchez
authors.forename: Concha
authors.initials: C
authors.lastname: Bailón
authors.forename: Beatriz
authors.initials: B
authors.lastname: Martín-Aznar
authors.forename: Javier
authors.initials: J
authors.lastname: Garzón
mesh_terms: D000818:Animals; D019281:Dimerization; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009020:Morphine / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D017434:Protein Structure, Tertiary; D020710:RGS Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: C489275:Hint1 protein, mouse; D009419:Nerve Tissue Proteins; D020710:RGS Proteins; D016194:Receptors, N-Methyl-D-Aspartate; D017450:Receptors, Opioid, mu; D009020:Morphine; D011493:Protein Kinase C