Comparison of the ORL1 receptor‐mediated inhibition of noradrenaline release in human and rat neocortical slices

The effects of nociceptin/orphanin (N/OFQ) and the selective ORL1 antagonist J‐113397 (1‐[(3R,4R)‐1‐cyclo‐octylmethyl‐3‐hydroxymethyl‐4‐piperidyl]‐3‐ethyl‐1,3‐dihydro‐2H‐benzimidazol‐2‐one) were studied on electrically‐evoked release of [ 3 H]‐noradrenaline ([ 3 H]‐NA) from human and rat neocortical slices. Specimens of human tissue were obtained during neurosurgery. Slices were preincubated with 0.1 μ M [ 3 H]‐NA, superfused in the presence of desipramine, idazoxan, and naloxone (1 μ M each), and stimulated electrically up to three times under conditions (4 pulses, 100 Hz, 2 ms, 60 mA) that prevent inhibition of evoked [ 3 H]‐NA release by endogenous modulators accumulating during ongoing stimulation. N/OFQ decreased electrically‐evoked [ 3 H]‐NA release in both human and rat neocortical slices in a concentration‐dependent manner. The respective pEC 50 values were 7.74 [CI 95 : 7.47, 8.04] and 7.64 [CI 95 : 7.48, 7.77], and the maximal inhibitions were 36.9%[CI 95 : 32.4%, 41.8%] and 66.4%[CI 95 : 61.7%, 72.7%]. N/OFQ (1 μ M ) inhibited K + (15 m M )‐evoked [ 3 H]‐NA release from neocortical slices of both species by a similar magnitude, either in the presence or absence of tetrodotoxin. The nonpeptide ORL1 antagonist J‐113397 competitively attenuated, with similar potency, the inhibition of electrically‐evoked [ 3 H]‐NA release by N/OFQ in both species (pA 2 values: human, 8.16 [CI 95 : 7.64, 8.64]; rat, 8.47 [CI 95 : 8.27, 8.67]). J‐113397 (0.1 μ M ) by itself did not alter either the evoked or spontaneous [ 3 H]‐NA release, suggesting that presynaptic ORL1 receptors are not activated by endogenous N/OFQ under the stimulation conditions employed. This study provides the first evidence that N/OFQ modulates [ 3 H]‐NA release in human neocortex via specific ORL1 receptors most likely located on noradrenergic axon terminals.British Journal of Pharmacology (2002) 135 , 800–806; doi: 10.1038/sj.bjp.0704523