Nociceptin/orphanin FQ decreases serotonin efflux in the rat brain but in contrast to a κ-opioid has no antagonistic effect on μ-opioid-induced increases in serotonin efflux

Similar to κ-opioids, nociceptin/orphanin FQ (OFQ) exerts anti-μ-opioid actions. This may involve interactions within the circuitry controlling 5-HT neurons in the dorsal raphe nucleus (DRN) that project to the nucleus accumbens (NAcc). To test this hypothesis, we compared the effects of OFQ and κ-opioids on 5-HT efflux in the CNS of freely behaving rats. First, OFQ (30-300 μM) infused into the DRN for 120 min dose-dependently decreased 5-HT efflux in the DRN. The opioid receptor-like 1 (ORL-1) antagonist [Nphe1]nociceptin(1-13)NH2 blocked this effect. Using dual-probe microdialysis we observed that OFQ (300 μM) infused into the DRN for 120 min produced parallel decreases in 5-HT efflux in the DRN and NAcc, suggesting that ORL-1 receptors in the DRN inhibit serotonergic neurons projecting to the NAcc. Also, 5-HT efflux in the NAcc was dose-dependently decreased during OFQ (30-300 μM) infusion into the NAcc. This suggests that OFQ can reduce 5-HT efflux in the NAcc both by inhibiting serotonergic neurons in the DRN and by stimulating ORL-1 receptors in the NAcc. Similar to OFQ, the κ-opioids U-50,488 (300 μM) and dynorphin A(1-13) (300 μM) infused into the DRN for 120 min decreased 5-HT efflux in the DRN. This effect was blocked only by the κ-opioid receptor antagonist nor-BNI. Lastly, we compared the ability of OFQ and U-50,488 to block μ-opioid-induced increases in 5-HT. The κ-opioid U-50,488 (1000 μM) attenuated the increase in 5-HT induced by the μ-opioid agonist endomorphin-1 (300 μM) in the DRN. In contrast, OFQ (300-1000 μM) did not alter μ-opioid-induced increases in 5-HT efflux. In summary, κ-opioids and OFQ both decreased 5-HT efflux in the CNS. However, in contrast to κ-opioids, which reversed μ-opioid-induced increases in 5-HT efflux, the anti-μ-opioid effects of OFQ apparently do not involve changes in 5-HT transmission under our experimental conditions.