Prodynorphin gene deficiency potentiates nalbuphine-induced behavioral sensitization and withdrawal syndrome in mice.
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.
Shin
Eun-Joo
EJ
Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon 200-701, Republic of Korea.
Jang
Choon-Gon
CG
Bing
Guoying
G
Park
Dae Hun
DH
Oh
Chang-Hyun
CH
Koo
Kyo Hwan
KH
Oh
Ki Wan
KW
Yamada
Kiyofumi
K
Nabeshima
Toshitaka
T
Kim
Hyoung-Chun
HC
D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / Q000494:pharmacology; D018712:Analgesics, Non-Narcotic / Q000494:pharmacology; D000701:Analgesics, Opioid; D000818:Animals; D019540:Area Under Curve; D015153:Blotting, Western; D004298:Dopamine / Q000378:metabolism; D004745:Enkephalins / Q000172:deficiency* / Q000235:genetics*; D015870:Gene Expression / Q000187:drug effects; D016762:Genes, fos / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D017551:Microdialysis; D009043:Motor Activity / Q000187:drug effects; D009266:Nalbuphine; D009270:Naloxone / Q000494:pharmacology; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D011498:Protein Precursors / Q000172:deficiency* / Q000235:genetics*; D017473:Receptors, Opioid, kappa / Q000235:genetics / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013375:Substance Withdrawal Syndrome / Q000235:genetics* / Q000523:psychology*
D018712:Analgesics, Non-Narcotic; D000701:Analgesics, Opioid; D004745:Enkephalins; D009292:Narcotic Antagonists; D011498:Protein Precursors; D017473:Receptors, Opioid, kappa; D009270:Naloxone; C051844:norbinaltorphimine; D009271:Naltrexone; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; C033660:preproenkephalin; D009266:Nalbuphine; D004298:Dopamine