Effect of fentanyl on 5-HT efflux involves both opioid and 5-HT1A receptors

1 Fentanyl is a m-opioid analgesic that might disinhibit 5-HT neurons and thus increase 5-HT efflux. However, fentanyl also binds to 5-HT1A receptors, and if it activates 5-HT1A somatodendritic autoreceptors, the resultant inhibition might offset opioid-mediated increases in 5-HT efflux. To test this hypothesis, we used microdialysis to study effects of fentanyl on extracellular 5-HT in the dorsal raphe nucleus (DRN) of unanesthetized rats. 2 Systemic administration of fentanyl (0.01–0.2mg kg1, s.c.) increased 5-HT efflux in the DRN. An intermediate dose of fentanyl (0.05mgkg1) produced the maximum increase in 5-HT to B180 % of baseline levels in the DRN. Naltrexone (10mg kg1, s.c.) blocked the increase in response to systemic fentanyl (0.05mg kg1). 3 In contrast, during infusion into the DRN, fentanyl (10–1000mm) induced a dose-dependent decrease in 5-HT. Naltrexone and nor-binaltorphimine failed to block the decrease suggesting that m-and k-opioid receptors did not mediate this effect. 4 Systemic ()-pindolol (8mg kg1, s.c.) or infusion of WAY-100635 (100 mm) into the DRN blocked the decrease, and instead 5-HT increased in response to local infusion of fentanyl (100 mm). WAY-100635 (0.3mg kg1, s.c.) also potentiated the effect of systemic fentanyl (0.2mgkg1, s.c.). ()