Nociceptin (orphanin FQ) is an endogenous peptide agonist for the newly discovered receptor (opioid receptor-like 1 receptor, ORL1) that bears striking homology to opioid receptors. Initial reports claimed that this peptide had hypoalgesic effects following i.c.v. or i.t. administration. The present study demonstrates that, in the presence of opioid receptor blockade, nociceptin can substantially alter the magnitude of the stimulated release of methionine-enkephalin from the guinea pig myenteric plexus. This effect is concentration dependent. Low doses (1 or 10 nM) inhibit whereas higher concentrations (100 or 1000 nM) enhance evoked enkephalin release. In contrast, in the absence of opioid receptor blockade, a statistically significant inhibition of stimulated enkephalin release is observed in response to 1, 100 or 1000 nM nociceptin. However, the magnitude of this effect did not differ among these concentrations. Furthermore, at 10 nM nociceptin, either an inhibition or enhancement of stimulated enkephalin release is manifest. The ability of naloxone to alter the nociceptin modulation of enkephalin release suggests that a component of the nociceptin modulation of enkephalin release is mediated via opioid receptors. This is consistent with the observation that this peptide has modest affinity for opioid receptors (L > K > 8) which, under appropriate conditions, should be sufficient to permit interactions with multiple opioid receptor types. This complicates dose responsiveness for nociceptin since both the naloxone-resistant (ORL1-mediated) and naloxone-sensitive (opioid receptor-mediated) component exhibit a concentration-dependent bimodality (albeit in opposite directions). Determination of i.c.v. or i.t. nociceptin dose responsiveness over several orders of magnitude is suggested before concluding the physiological effects of this peptide.