Nociceptin/orphanin FQ decreases serotonin efflux in the rat brain but in contrast to a kappa-opioid has no antagonistic effect on mu-opioid-induced increases in serotonin efflux.
Similar to kappa-opioids, nociceptin/orphanin FQ (OFQ) exerts anti-mu-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 kappa-opioids on 5-HT efflux in the CNS of freely behaving rats. First, OFQ (30-300 microM) infused into the DRN for 120 min dose-dependently decreased 5-HT efflux in the DRN. The opioid receptor-like 1 (ORL-1) antagonist [Nphe(1)]nociceptin(1-13)NH(2) blocked this effect. Using dual-probe microdialysis we observed that OFQ (300 microM) 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 microM) 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 kappa-opioids U-50,488 (300 microM) and dynorphin A(1-13) (300 microM) infused into the DRN for 120 min decreased 5-HT efflux in the DRN. This effect was blocked only by the kappa-opioid receptor antagonist nor-BNI. Lastly, we compared the ability of OFQ and U-50,488 to block mu-opioid-induced increases in 5-HT. The kappa-opioid U-50,488 (1000 microM) attenuated the increase in 5-HT induced by the mu-opioid agonist endomorphin-1 (300 microM) in the DRN. In contrast, OFQ (300-1000 microM) did not alter mu-opioid-induced increases in 5-HT efflux. In summary, kappa-opioids and OFQ both decreased 5-HT efflux in the CNS. However, in contrast to kappa-opioids, which reversed mu-opioid-induced increases in 5-HT efflux, the anti-mu-opioid effects of OFQ apparently do not involve changes in 5-HT transmission under our experimental conditions.
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Department of Biomedical Sciences, Florida Atlantic University, 777 Glades Road, Boca Raton, FL 33431, USA. rtao@fau.edu
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D000818:Animals; D004305:Dose-Response Relationship, Drug; D008297:Male; D017551:Microdialysis; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009714:Nucleus Accumbens / Q000378:metabolism*; D018847:Opioid Peptides / Q000008:administration & dosage / Q000502:physiology*; D011903:Raphe Nuclei / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017473:Receptors, Opioid, kappa / Q000819:agonists / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism*; D000097629:Nociceptin
D009271:Naltrexone; D009292:Narcotic Antagonists; D018847:Opioid Peptides; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D012701:Serotonin; D000097629:Nociceptin; C051844:norbinaltorphimine