Enhanced spinal nociceptin receptor expression develops morphine toleranceand dependence

The tolerance and dependence after chronic medication with morphine are tho ught to be representative models for studying the plasticity, including the remodeling of neuronal networks. To test the hypothesis that changes in ne uronal plasticity observed in opioid tolerance or dependence are derived fr om increased activity of the anti-opioid nociceptin system, the effects of chronic treatments with morphine were examined using nociceptin receptor kn ock-out (NOR-/-) mice and a novel nonpeptidic NOR antagonist, J-113397, whi ch shows a specific and potent NOR antagonist activity in in vitro [S-35] G TP gamma S binding assay and in vivo peripheral nociception test. The NOR-/ - mice showed marked resistance to morphine analgesic tolerance without aff ecting morphine analgesic potency in tail-pinch and tail-flick tests. The N OR-/- mice also showed marked attenuation of morphine-induced physical depe ndence, manifested as naloxone-precipitated withdrawal symptoms after repea ted morphine treatments. Similar marked attenuation of morphine tolerance w as 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 morph ine-treated ddY mice. However, the intracerebroventricular injection (up to 3 nmol) did not affect the tolerance. On the other hand, morphine dependen ce was markedly attenuated by J-113397 that had been subcutaneously given 6 0 min before naloxone challenge. There was also observed a parallel enhance ment of NOR gene expression only in the spinal cord during chronic morphine treatments. Together, these findings suggest that the spinal NOR system de velops anti-opioid plasticity observed on morphine tolerance and dependence .