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

Javier Garzón; Raquel Herrero-Labrador; María Rodríguez-Muñoz; Rachit Shah; Ana Vicente-Sánchez; Carston R. Wagner; Pilar Sánchez-Blázquez

doi:10.1016/j.neuropharm.2014.10.022

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

Javier Garzón, Raquel Herrero-Labrador, María Rodríguez-Muñoz, Rachit Shah, Ana Vicente-Sánchez, Carston R. Wagner, Pilar Sánchez-Blázquez

Medicinal Chemistry

Research output: Contribution to journal › Article › peer-review

34 Scopus citations

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.

Original language	English (US)
Pages (from-to)	412-423
Number of pages	12
Journal	Neuropharmacology
Volume	89
DOIs	https://doi.org/10.1016/j.neuropharm.2014.10.022
State	Published - Feb 2015

Bibliographical note

Funding Information:
We would like to thank Gabriela de Alba and Carmelo Aguado for their excellent technical assistance. This research was supported by MSC ‘Plan de Drogas 2011–14’ and the Ministerio de Economía y Competividad (MINECO) , SAF 2012-34991 . The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors have no conflicts of interest. CRW also wish to thank the University of Minnesota Foundation for partial support of this research.

Publisher Copyright:
© 2014 Elsevier Ltd. All rights reserved.

Keywords

Antinociception
Glutamate N-methyl-D-aspartate receptor
Guanosine-5′-tryptamine carbamate
Histidine triad nucleotide binding protein 1
Mu-opioid receptor
PKCγ
Receptor desensitization

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10.1016/j.neuropharm.2014.10.022

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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.",

keywords = "Antinociception, Glutamate N-methyl-D-aspartate receptor, Guanosine-5′-tryptamine carbamate, Histidine triad nucleotide binding protein 1, Mu-opioid receptor, PKCγ, Receptor desensitization",

author = "Javier Garz{\'o}n and Raquel Herrero-Labrador and Mar{\'i}a Rodr{\'i}guez-Mu{\~n}oz and Rachit Shah and Ana Vicente-S{\'a}nchez and Wagner, {Carston R.} and Pilar S{\'a}nchez-Bl{\'a}zquez",

note = "Funding Information: We would like to thank Gabriela de Alba and Carmelo Aguado for their excellent technical assistance. This research was supported by MSC {\textquoteleft}Plan de Drogas 2011–14{\textquoteright} and the Ministerio de Econom{\'i}a y Competividad (MINECO) , SAF 2012-34991 . The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors have no conflicts of interest. CRW also wish to thank the University of Minnesota Foundation for partial support of this research. Publisher Copyright: {\textcopyright} 2014 Elsevier Ltd. All rights reserved.",

year = "2015",

month = feb,

doi = "10.1016/j.neuropharm.2014.10.022",

language = "English (US)",

volume = "89",

pages = "412--423",

journal = "Neuropharmacology",

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T2 - A new therapeutic target to enhance opioid antinociception and block mechanical allodynia

AU - Garzón, Javier

AU - Herrero-Labrador, Raquel

AU - Rodríguez-Muñoz, María

AU - Shah, Rachit

AU - Vicente-Sánchez, Ana

AU - Wagner, Carston R.

AU - Sánchez-Blázquez, Pilar

N1 - Funding Information: We would like to thank Gabriela de Alba and Carmelo Aguado for their excellent technical assistance. This research was supported by MSC ‘Plan de Drogas 2011–14’ and the Ministerio de Economía y Competividad (MINECO) , SAF 2012-34991 . The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors have no conflicts of interest. CRW also wish to thank the University of Minnesota Foundation for partial support of this research. Publisher Copyright: © 2014 Elsevier Ltd. All rights reserved.

PY - 2015/2

Y1 - 2015/2

N2 - 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.

AB - 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.

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KW - Glutamate N-methyl-D-aspartate receptor

KW - Guanosine-5′-tryptamine carbamate

KW - Histidine triad nucleotide binding protein 1

KW - Mu-opioid receptor

KW - PKCγ

KW - Receptor desensitization

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DO - 10.1016/j.neuropharm.2014.10.022

M3 - Article

C2 - 25445489

AN - SCOPUS:84918511513

SN - 0028-3908

VL - 89

SP - 412

EP - 423

JO - Neuropharmacology

JF - Neuropharmacology

ER -

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

Abstract

Bibliographical note

Keywords

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