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.
|Number of pages||10|
|Journal||Drug and Alcohol Dependence|
|State||Published - Sep 1 2009|
Bibliographical noteFunding 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.
- In vivo microdialysis
- Prodynorphin gene knock-out mouse
- Withdrawal signs
ASJC Scopus subject areas
- Psychiatry and Mental health
- Pharmacology (medical)