Presynaptic opioid receptors on noradrenergic and serotonergic neurons in the human as compared to the rat neocortex

1 Electrically evoked release of [ 3 H]‐noradrenaline ([ 3 H]‐NA) or [ 3 H]‐5‐hydroxytryptamine ([ 3 H]‐5‐HT) in slices of human and the rat neocortex was used to characterize presynaptic opioid receptors. 2 Release of [ 3 H]‐NA in rat neocortical slices was reduced only by the μ ‐receptor agonist DAMGO (pIC 50 : 7.27, CI 95 : [7.22, 7.32]; I max : 77.6±1.6%; antagonized by naloxone: pA 2 : 8.88, CI 95 : [8.78, 8.98]). 3 Release of [ 3 H]‐NA in human neocortical slices was unaffected by DAMGO, but inhibited by the δ ‐receptor agonist DPDPE ( I max : 25.7±2.2%) and the κ ‐receptor agonist U‐50,488H (19.7±2.7% inhibition at 1  μ M ). Both effects were antagonized by naltrindole (1  μ M ). 4 Release of [ 3 H]‐5‐HT in rat neocortical slices, was inhibited by DAMGO (10  μ M ) and U‐50,488H (1 and 10  μ M ) only in the presence of the 5‐HT receptor antagonist methiotepin (1  μ M ). 5 Release of [ 3 H]‐5‐HT in human neocortical slices was unaffected by DPDPE, but U‐50,488H ( I max : 40.8±8.3%; antagonized by 0.1  μ M norbinaltorphimine) and DAMGO (16.4±3.9% inhibition at 1  μ M ; antagonized by 0.1  μ M naloxone) acted inhibitory. 6 Release of [ 3 H]‐5‐HT in human neocortical slices was reduced by nociceptin/orphanin (0.1 and 1  μ M ). These effects were antagonized by the ORL1 antagonist J‐113397 (1‐[(3R,4R)‐1‐cyclo‐octylmethyl‐3‐hydroxymethyl‐4‐piperidyl]‐3‐ethyl‐1,3‐dihydro‐2H‐benzimidazol‐2‐one; 0.1  μ M ). 7 This study provides evidence for significant species differences in opioid receptor‐mediated modulation of NA and 5‐HT‐release in human vs rat neocortex. In rats , μ ‐opioid receptors modulate NA release, but 5‐HT release is only weakly affected by μ ‐ and κ ‐opioids. In contrast, NA release in human neocortex is modulated via δ ‐opioid receptors, but 5‐HT release mainly via κ ‐opioid receptors. In addition also the ORL1 receptor seems to be involved in 5‐HT release modulation.British Journal of Pharmacology (2006) 148 , 795–806. doi: 10.1038/sj.bjp.0706782