Blockade of orexin type 1 receptors inhibits the development of morphine tolerance in lateral paragigantocellularis nucleus: An electrophysiological approach

Abstract

Repetitive administration of opioid agonists is associated with the development of tolerance to the effects of these substances and limits their application. Orexin (also known as hypocretin) is involved in morphine tolerance and dependence. The lateral paragigantocellularis nucleus (LPGi) is a key brain region implicated in the tolerance and dependence to opiates. Orexin type 1 receptor (OXR1) has been detected in LPGi nucleus. In this study the effect of OXR1 blockade was investigated on neural activity of LPGi during the development of morphine tolerance in rats. Male Wistar rats weighing 250–300g were used in this study. To incite tolerance, morphine sulfate was injected intraperitonealy (10mg/kg, i.p.) once a day for 6 days. A selective OXR1 antagonist (SB-334867) was microinjected into the right cerebral ventricle (10μg/10μl, i.c.v.) immediately before each morphine injection. On day 7, the effect of morphine (10mg/kg, i.p.) on neural activity of LPGi was investigated using in vivo extracellular single unit recording. In this study morphine injection during 6 days led to the development of morphine tolerance in LPGi neurons which was observed as a significant decrease in responsiveness of LPGi neurons to acute morphine injection. Administration of SB-334867 before each morphine injection could reverse the responses of LPGi neurons to acute morphine injection. This study showed that OXR1 blockade by SB-334867 prevents the development of tolerance to morphine in LPGi neurons. Further studies are required to determine molecular and anatomical mediators which are thought to be involved in this phenomenon.