Enhancement of -Opioid Receptor Desensitization by Nitric Oxide in Rat Locus Coeruleus Neurons: Involvement of Reactive Oxygen Species

It has previously been shown that nitric oxide (NO) synthase is involved in the development of opioid tolerance. The aim of the present work was to study the effect of NO on -opioid recep-tor (MOR) desensitization. Furthermore, we explored the pos-sible role of reactive oxygen species (ROS) in this effect. Single-unit extracellular and whole-cell patch-clamp recordings were performed on locus coeruleus (LC) neurons from rat brain slices. Perfusion with high concentrations of Met5-enkephalin (ME) caused a concentration-related reduction of opioid effect, reflecting the induction of homologous MOR desensitization. The NO donors sodium nitroprusside and diethylamine NONO-ate markedly enhanced the ME-induced MOR desensitization, although the acute effect of ME on K conductance was not affected by sodium nitroprusside.Continuous perfusion with the antioxidants melatonin, trolox, 21-[4-(2,6-di-1-pyrrolidinyl-4-pyrrimidinyl)-1-piperazinyl]-pregna-1,4,9(11)-triene-3,20-dione(Z)-2-butenedioate (U74389G), and diethyldithiocarbamate pre-vented the effect of sodium nitroprusside on MOR desensitization, but they did not themselves alter the desensi-tization. Like sodium nitroprusside, the ROS-generating mole-cule H2O2 enhanced MOR desensitization induced by ME. However, 2-adrenoceptor desensitization induced by nor-adrenaline was not modified by H2O2, suggesting a selective action of ROS on MOR. Our results suggest that elevated levels of NO, which may be reached in pathological processes, en-hance homologous desensitization of MOR in the LC, probably through a mechanism involving ROS generation