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The histidine triad nucleotide-binding protein 1 supports mu-opioid receptor–glutamate NMDA receptor cross-regulation

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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.

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Abbreviations

BiFC:

Bimolecular fluorescence complementation

CaMKII:

Calcium and calmodulin-dependent serine threonine kinase II

GPCR:

G protein-coupled receptor

HINT1:

Histidine triad nucleotide-binding protein 1

ICV:

Intracerebroventricular

MOR:

Mu opioid receptor

NMDAR:

N-methyl-d-aspartate receptor

nNOS:

Neural nitric oxide synthase

NO:

Nitric oxide

ODN:

Oligodeoxynucleotide

PAG:

Periaqueductal gray matter

PKC:

Protein kinase C

PKCI:

Protein kinase C-interacting protein

RGS:

Regulator of G-protein signaling

SPR:

Surface plasmon resonance

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Acknowledgments

MRM and BMA are members of the Centro de Investigación Biomédica en Red de Salud Mental CIBERSAM. AVS is a predoctoral fellow from Ministerio de Educación y Ciencia (FPI, BES-2007-17162). We would like to thank Beatriz Fraile for her excellent technical support. These studies were supported by the Instituto de Salud Carlos III (PI08-0417 and PS09/00332).

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Correspondence to Javier Garzón.

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Rodríguez-Muñoz, M., Sánchez-Blázquez, P., Vicente-Sánchez, A. et al. The histidine triad nucleotide-binding protein 1 supports mu-opioid receptor–glutamate NMDA receptor cross-regulation. Cell. Mol. Life Sci. 68, 2933–2949 (2011). https://doi.org/10.1007/s00018-010-0598-x

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