Fentanyl and sufentanil inhibit agonist binding to 5-HT_1A receptors in membranes from the rat brain

The influence of several opioid narcotics and related drugs, on the binding of [³H]8-hydroxy-N,N-dipropyl-2-aminotetralin ([³H]8-OH-DPAT), a serotonergic agonist, to 5-HT_1A receptors was determined in membranes from the brain of the rat. Sufentanil and fentanyl inhibited binding of [³H]8-OH-DPAT to hippocampal membranes, with IC₅₀ values of 5.5 and 3.4 μM, respectively. In contrast, IC₅₀ values for meperidine, alfentanil and naloxone exceeded 100 μM. The inhibition of binding by sufentanil appeared to be competitive insofar as 10 μM sufentanil increased the apparent K_D from 1.0 ± 0.1 to 3.9 ± 0.3 nM, without affecting the number of binding sites and the inhibition was easily reversed. The binding of [³H]8-OH-DPAT to hippocampal membranes was inhibited by 5′-guanylylimidodiphosphate, a stable analogue of GTP, in a concentration-dependent manner. None of the opioid drugs examined altered the sensitivity of binding of [³H]8-OH-DPAT to guanine nucleotides. These results suggest that certain opioid narcotics, disrupt serotonergic neurotransmission as a result of direct interactions with 5-HT_1A receptors. No effects of opioid narcotics on 5-HT_1A receptor-G protein coupling were noted.