Prodynorphin gene deficiency potentiates nalbuphine-induced behavioral sensitization and withdrawal syndrome in mice

Eun Joo Shin; Choon Gon Jang; Guoying Bing; Dae Hun Park; Chang Hyun Oh; Kyo Hwan Koo; Ki Wan Oh; Kiyofumi Yamada; Toshitaka Nabeshima; Hyoung Chun Kim

doi:10.1016/j.drugalcdep.2009.05.015

Prodynorphin gene deficiency potentiates nalbuphine-induced behavioral sensitization and withdrawal syndrome in mice

Eun Joo Shin, Choon Gon Jang, Guoying Bing, Dae Hun Park, Chang Hyun Oh, Kyo Hwan Koo, Ki Wan Oh, Kiyofumi Yamada, Toshitaka Nabeshima, Hyoung Chun Kim

Neuroscience

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

6 Scopus citations

Abstract

Dynorphin is the presumed endogenous ligand for the kappa-opioid receptor. The dynorphin gene may play a role in psychotropic agent-mediated behavioral changes via dopaminergic modulation. Therefore, in this study, possible involvement of the dynorphin gene in nalbuphine-mediated behavioral responses was examined using prodynorphin (Pdyn) gene knock-out (-/-) mice. Pdyn gene deficiency potentiates nalbuphine-induced behavioral sensitization of locomotor activity and accumbal c-Fos expression. Administration of nalbuphine induced a significant increase in the dialysate dopamine level in the nucleus accumbens. This increase was more pronounced in the Pdyn (-/-) mice than in the wild-type (WT) mice. In addition, Pdyn (-/-) mice were more vulnerable to the naloxone-precipitated withdrawal syndrome (i.e., teeth chattering, wet dog shakes, forepaw tremors, jumping, weight loss, and global withdrawal score) after repeated treatment with nalbuphine than the WT mice. Consistently, nor-binaltorphimine, a kappa-opioid receptor antagonist, significantly potentiated nalbuphine-induced behavioral effects in WT mice, whereas U-50488H, a kappa-opioid receptor agonist, significantly attenuated these changes in Pdyn (-/-) mice in a dose-dependent manner. Our data suggest that the kappa-opioid receptor/dynorphin system is specifically modulated in response to behavioral sensitization and withdrawal signs induced by nalbuphine.

Original language	English
Pages (from-to)	175-184
Number of pages	10
Journal	Drug and Alcohol Dependence
Volume	104
Issue number	1-2
DOIs	https://doi.org/10.1016/j.drugalcdep.2009.05.015
State	Published - Sep 1 2009

Bibliographical note

Funding Information:
This study was supported by a grant (2009K001253) from the Brain Research Center from 21st Century Frontier Research Program funded by the Ministry of Science and Technology, Republic of Korea, by a grant from Academic Frontier Project for Private Universities (2007–2011) from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and by a grant of the Korea–Japan Joint Research Program (F01-2007-000-10165-0), Korea Science and Engineering Foundation (KOSEF). Kyo Hwan Koo was supported by BK 21 program. The funding sources had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the paper for publication.

Keywords

In vivo microdialysis
Nalbuphine
Prodynorphin gene knock-out mouse
Rewarding
Withdrawal signs

ASJC Scopus subject areas

Toxicology
Pharmacology
Psychiatry and Mental health
Pharmacology (medical)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.drugalcdep.2009.05.015

Cite this

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title = "Prodynorphin gene deficiency potentiates nalbuphine-induced behavioral sensitization and withdrawal syndrome in mice",

abstract = "Dynorphin is the presumed endogenous ligand for the kappa-opioid receptor. The dynorphin gene may play a role in psychotropic agent-mediated behavioral changes via dopaminergic modulation. Therefore, in this study, possible involvement of the dynorphin gene in nalbuphine-mediated behavioral responses was examined using prodynorphin (Pdyn) gene knock-out (-/-) mice. Pdyn gene deficiency potentiates nalbuphine-induced behavioral sensitization of locomotor activity and accumbal c-Fos expression. Administration of nalbuphine induced a significant increase in the dialysate dopamine level in the nucleus accumbens. This increase was more pronounced in the Pdyn (-/-) mice than in the wild-type (WT) mice. In addition, Pdyn (-/-) mice were more vulnerable to the naloxone-precipitated withdrawal syndrome (i.e., teeth chattering, wet dog shakes, forepaw tremors, jumping, weight loss, and global withdrawal score) after repeated treatment with nalbuphine than the WT mice. Consistently, nor-binaltorphimine, a kappa-opioid receptor antagonist, significantly potentiated nalbuphine-induced behavioral effects in WT mice, whereas U-50488H, a kappa-opioid receptor agonist, significantly attenuated these changes in Pdyn (-/-) mice in a dose-dependent manner. Our data suggest that the kappa-opioid receptor/dynorphin system is specifically modulated in response to behavioral sensitization and withdrawal signs induced by nalbuphine.",

keywords = "In vivo microdialysis, Nalbuphine, Prodynorphin gene knock-out mouse, Rewarding, Withdrawal signs",

author = "Shin, {Eun Joo} and Jang, {Choon Gon} and Guoying Bing and Park, {Dae Hun} and Oh, {Chang Hyun} and Koo, {Kyo Hwan} and Oh, {Ki Wan} and Kiyofumi Yamada and Toshitaka Nabeshima and Kim, {Hyoung Chun}",

note = "Funding Information: This study was supported by a grant (2009K001253) from the Brain Research Center from 21st Century Frontier Research Program funded by the Ministry of Science and Technology, Republic of Korea, by a grant from Academic Frontier Project for Private Universities (2007–2011) from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and by a grant of the Korea–Japan Joint Research Program (F01-2007-000-10165-0), Korea Science and Engineering Foundation (KOSEF). Kyo Hwan Koo was supported by BK 21 program. The funding sources had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the paper for publication. ",

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doi = "10.1016/j.drugalcdep.2009.05.015",

language = "English",

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T1 - Prodynorphin gene deficiency potentiates nalbuphine-induced behavioral sensitization and withdrawal syndrome in mice

AU - Shin, Eun Joo

AU - Jang, Choon Gon

AU - Bing, Guoying

AU - Park, Dae Hun

AU - Oh, Chang Hyun

AU - Koo, Kyo Hwan

AU - Oh, Ki Wan

AU - Yamada, Kiyofumi

AU - Nabeshima, Toshitaka

AU - Kim, Hyoung Chun

N1 - Funding Information: This study was supported by a grant (2009K001253) from the Brain Research Center from 21st Century Frontier Research Program funded by the Ministry of Science and Technology, Republic of Korea, by a grant from Academic Frontier Project for Private Universities (2007–2011) from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and by a grant of the Korea–Japan Joint Research Program (F01-2007-000-10165-0), Korea Science and Engineering Foundation (KOSEF). Kyo Hwan Koo was supported by BK 21 program. The funding sources had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the paper for publication.

PY - 2009/9/1

Y1 - 2009/9/1

N2 - Dynorphin is the presumed endogenous ligand for the kappa-opioid receptor. The dynorphin gene may play a role in psychotropic agent-mediated behavioral changes via dopaminergic modulation. Therefore, in this study, possible involvement of the dynorphin gene in nalbuphine-mediated behavioral responses was examined using prodynorphin (Pdyn) gene knock-out (-/-) mice. Pdyn gene deficiency potentiates nalbuphine-induced behavioral sensitization of locomotor activity and accumbal c-Fos expression. Administration of nalbuphine induced a significant increase in the dialysate dopamine level in the nucleus accumbens. This increase was more pronounced in the Pdyn (-/-) mice than in the wild-type (WT) mice. In addition, Pdyn (-/-) mice were more vulnerable to the naloxone-precipitated withdrawal syndrome (i.e., teeth chattering, wet dog shakes, forepaw tremors, jumping, weight loss, and global withdrawal score) after repeated treatment with nalbuphine than the WT mice. Consistently, nor-binaltorphimine, a kappa-opioid receptor antagonist, significantly potentiated nalbuphine-induced behavioral effects in WT mice, whereas U-50488H, a kappa-opioid receptor agonist, significantly attenuated these changes in Pdyn (-/-) mice in a dose-dependent manner. Our data suggest that the kappa-opioid receptor/dynorphin system is specifically modulated in response to behavioral sensitization and withdrawal signs induced by nalbuphine.

AB - Dynorphin is the presumed endogenous ligand for the kappa-opioid receptor. The dynorphin gene may play a role in psychotropic agent-mediated behavioral changes via dopaminergic modulation. Therefore, in this study, possible involvement of the dynorphin gene in nalbuphine-mediated behavioral responses was examined using prodynorphin (Pdyn) gene knock-out (-/-) mice. Pdyn gene deficiency potentiates nalbuphine-induced behavioral sensitization of locomotor activity and accumbal c-Fos expression. Administration of nalbuphine induced a significant increase in the dialysate dopamine level in the nucleus accumbens. This increase was more pronounced in the Pdyn (-/-) mice than in the wild-type (WT) mice. In addition, Pdyn (-/-) mice were more vulnerable to the naloxone-precipitated withdrawal syndrome (i.e., teeth chattering, wet dog shakes, forepaw tremors, jumping, weight loss, and global withdrawal score) after repeated treatment with nalbuphine than the WT mice. Consistently, nor-binaltorphimine, a kappa-opioid receptor antagonist, significantly potentiated nalbuphine-induced behavioral effects in WT mice, whereas U-50488H, a kappa-opioid receptor agonist, significantly attenuated these changes in Pdyn (-/-) mice in a dose-dependent manner. Our data suggest that the kappa-opioid receptor/dynorphin system is specifically modulated in response to behavioral sensitization and withdrawal signs induced by nalbuphine.

KW - In vivo microdialysis

KW - Nalbuphine

KW - Prodynorphin gene knock-out mouse

KW - Rewarding

KW - Withdrawal signs

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Prodynorphin gene deficiency potentiates nalbuphine-induced behavioral sensitization and withdrawal syndrome in mice

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

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