Plasma level of nociceptin, the endogenous agonists of orphaninFQ/OP4 receptor was found to be significantly elevated in Wilson's disease patients (14.87 +/- 2.44 pg/ml +/- SD, p < 0.001, n = 21) compared to age-matched healthy controls (9.18 +/- 1.63 pg/ml +/- SD, n = 25). Wilson's disease is an autosomal recessive disorder caused by mutation of the gene ATP7B leading to toxic copper accumulation mainly in the liver and brain and in other organs such as, kidney and cornea. Measurements were performed by 125I-radioimmunoassay. Neither sex differences nor correlation between plasma nociceptin levels and liver function test results were found in Wilson's disease patients. It is suggested that significantly elevated plasma nociceptin level is due to the inhibition of nociceptin-inactivating Zn-metallopeptidases (aminopeptidase N, endopeptidase 24.15) by the toxic copper levels, as it is known that changing the central Zn atom to Cu results in an approximately 50% inhibition in the activity of these enzymes. The high plasma nociceptin level in Wilson's disease patients may induce significant impairment in nociceptinerg neurotransmission.