3H]Ohmefentanyl preferentially binds to μ-opioid receptors but also labels σ-sites in rat brain sections

Abstract

Ohmefentanyl has been shown to be 6300 times more potent than morphine for analgesia. The receptor binding characteristics and distribution of [ 3H]ohmefentanyl in rat brain sections are presented. [ 3H]Ohmefentanyl bound with high affinity to opioid receptors in a saturable manner (K d = 0.95 ± 0.08 nM, B max = 337 ± 14 fmol/mg protein). We used various currently available specific μ, δ and k ligands to show that [ 3H]ohmefentanyl has a high selectivity for the μ opioid receptor. However, [D-Ala 2,MePhe 4,Gly-ol 5]enkephalin (DAGO) was unable to completely inhibit [ 3H]ohmefentanyl specific binding, while complete inhibition was observed with fentanyl derivatives and the benzomorphan derivative, ethylketocyclazocine. This remaining 20% DAGO-inaccessible [ 3H]ohmefentanyl specific binding did not correspond to either μ 1, δ or k sites. Haloperidol and 1,3-di-otolylguanidine were able to inhibit DAGO-inaccessible [ 3H]ohmefentanyl specific binding suggesting that [ 3H]ohmefentanyl might also bind to haloperidol-sensitive σ sites. The topographical distribution of [ 3H]ohmefentanyl found by autoradiography was generally similar to that of [ 3H]DAGO. However, in agreement with the biochemical results, quantitative analysis revealed additional sites in several rat brain regions, the greatest discrepancies with [ 3H]DAGO distribution being observed in cerebellum, central grey, hippocampal formation and locus coeruleus. Finally, our results suggest that this capacity of binding to both μ and σ sites is shared by various fentanyl derivatives.