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

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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 languageEnglish
Pages (from-to)175-184
Number of pages10
JournalDrug and Alcohol Dependence
Volume104
Issue number1-2
DOIs
Publication statusPublished - 01-09-2009

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All Science Journal Classification (ASJC) codes

  • Toxicology
  • Pharmacology
  • Psychiatry and Mental health
  • Pharmacology (medical)

Cite this

Shin, E. J., Jang, C. G., Bing, G., Park, D. H., Oh, C. H., Koo, K. H., Oh, K. W., Yamada, K., Nabeshima, T., & Kim, H. C. (2009). Prodynorphin gene deficiency potentiates nalbuphine-induced behavioral sensitization and withdrawal syndrome in mice. Drug and Alcohol Dependence, 104(1-2), 175-184. https://doi.org/10.1016/j.drugalcdep.2009.05.015