Long-term exposure to opioid antagonists up-regulates prodynorphin gene expression in rat brain.
We investigated the effect of long-term administration of opioid antagonists on the regulation of prodynorphin gene expression in rat brain. Intracerebroventricular (i.c.v.) injections for seven days of nor-binaltorphimine (nor-BNI), the highly selective kappa opioid antagonist, naloxone and its longer acting analog naltrexone, both relatively selective antagonists for the mu opioid receptor, markedly raised prodynorphin mRNA levels in rat hypothalamus, hippocampus and striatum. Peptides, namely immunoreactive-dynorphin A (ir-dyn A), were unaffected after chronic treatment with all antagonists, in the same tissues. These results, taken together with our previous observations, suggest that chronic opioid antagonists, acting on kappa and mu opioid receptors, clearly up-regulate prodynorphin gene expression in discrete rat brain regions, activating its biosynthesis. Moreover, our data support the hypothesis that the endogenous opioid system plays a role in the mechanisms underlying the development of opiate tolerance.
Romualdi
P
P
Department of Pharmacology, University of Bologna, Italy.
Lesa
G
G
Donatini
A
A
Ferri
S
S
D000818:Animals; D001921:Brain / Q000502:physiology*; D004745:Enkephalins / Q000235:genetics*; D015870:Gene Expression / Q000187:drug effects*; D008297:Male; D009270:Naloxone / Q000494:pharmacology; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology*; D011498:Protein Precursors / Q000235:genetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
D004745:Enkephalins; D009292:Narcotic Antagonists; D011498:Protein Precursors; D009270:Naloxone; C051844:norbinaltorphimine; D009271:Naltrexone; C033660:preproenkephalin