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The Journal of Neuroscience, October 15, 2000, 20(20):7640-7647
Enhanced Spinal Nociceptin Receptor Expression Develops Morphine
Tolerance and Dependence
Hiroshi
Ueda1,
Makoto
Inoue1,
Hiroshi
Takeshima2, and
Yoshikazu
Iwasawa3
1 Department of Molecular Pharmacology and
Neuroscience, Nagasaki University School of Pharmaceutical Sciences,
Nagasaki 852-8521, Japan, 2 Department of Pharmacology,
Faculty of Medicine, The University of Tokyo, Tokyo 113-0033, Japan,
and 3 Banyu Tsukuba Research Institute, 3 Okubo Tsukuba,
300-2611, Japan
The tolerance and dependence after chronic medication with morphine
are thought to be representative models for studying the plasticity,
including the remodeling of neuronal networks. To test the hypothesis
that changes in neuronal plasticity observed in opioid tolerance or
dependence are derived from increased activity of the anti-opioid
nociceptin system, the effects of chronic treatments with morphine were
examined using nociceptin receptor knock-out (NOR /) mice and a novel nonpeptidic NOR
antagonist, J-113397, which shows a specific and potent NOR antagonist
activity in in vitro [35S]GTP S
binding assay and in vivo peripheral nociception
test. The NOR/ mice showed marked resistance to
morphine analgesic tolerance without affecting morphine analgesic
potency in tail-pinch and tail-flick tests. The
NOR/ mice also showed marked attenuation of
morphine-induced physical dependence, manifested as
naloxone-precipitated withdrawal symptoms after repeated morphine
treatments. Similar marked attenuation of morphine tolerance was also
observed by single subcutaneous (10 mg/kg) or intrathecal (1 nmol)
injection of J-113397, which had been given 60 min before the test in
morphine-treated ddY mice. However, the intracerebroventricular
injection (up to 3 nmol) did not affect the tolerance. On the other
hand, morphine dependence was markedly attenuated by J-113397 that had
been subcutaneously given 60 min before naloxone challenge. There was
also observed a parallel enhancement of NOR gene expression only
in the spinal cord during chronic morphine treatments. Together, these
findings suggest that the spinal NOR system develops anti-opioid
plasticity observed on morphine tolerance and dependence.
Key words:
nociceptin/orphanin FQ; morphine; tolerance; dependence; plasticity; nonpeptidic antagonist
Copyright © 2000 Society for Neuroscience 0270-6474/00/20207640-08$05.00/0
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