期刊
CELLULAR AND MOLECULAR LIFE SCIENCES
卷 68, 期 17, 页码 2933-2949出版社
SPRINGER BASEL AG
DOI: 10.1007/s00018-010-0598-x
关键词
Histidine triad nucleotide-binding protein 1; Mu-opioid receptor; Glutamate N-methyl-D-aspartate receptor; PKC gamma; Receptor desensitization; Analgesia; Regulator of G-protein signaling RGSZ2(17) protein
资金
- Instituto de Salud Carlos III [PI08-0417, PS09/00332]
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.
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