Effect of fentanyl on 5‐HT efflux involves both opioid and 5‐HT 1A receptors

Fentanyl is a μ ‐opioid analgesic that might disinhibit 5‐HT neurons and thus increase 5‐HT efflux. However, fentanyl also binds to 5‐HT 1A receptors, and if it activates 5‐HT 1A 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. Systemic administration of fentanyl (0.01–0.2 mg kg −1 , s.c.) increased 5‐HT efflux in the DRN. An intermediate dose of fentanyl (0.05 mg kg −1 ) produced the maximum increase in 5‐HT to ∼180% of baseline levels in the DRN. Naltrexone (10 mg kg −1 , s.c.) blocked the increase in response to systemic fentanyl (0.05 mg kg −1 ). In contrast, during infusion into the DRN, fentanyl (10–1000 μ M ) induced a dose‐dependent decrease in 5‐HT. Naltrexone and nor ‐binaltorphimine failed to block the decrease suggesting that μ ‐ and κ ‐opioid receptors did not mediate this effect. Systemic (−)‐pindolol (8 mg kg −1 , s.c.) or infusion of WAY‐100635 (100 μ M ) into the DRN blocked the decrease, and instead 5‐HT increased in response to local infusion of fentanyl (100 μ M ). WAY‐100635 (0.3 mg kg −1 , s.c.) also potentiated the effect of systemic fentanyl (0.2 mg kg −1 , s.c.). (−)‐Pindolol and WAY‐100635 block 5HT 1A receptors, indicating that inhibition of 5‐HT neuronal activity resulting from fentanyl binding to somatodendritic autoreceptors attenuated opioid‐mediated increases in 5‐HT efflux. These results provide novel evidence that besides stimulating μ ‐opioid receptors, fentanyl is a 5‐HT 1A receptor agonist. Possibly, this contributes to lethality of fentanyl overdose. British Journal of Pharmacology (2003) 139 , 1498–1504. doi: 10.1038/sj.bjp.0705378