Chronic adolescent morphine exposure alters the responses of lateral paragigantocellular neurons to acute morphine administration in adulthood.

Accumulating evidence support the growing non-medical use of morphine during adolescence. Despite this concern which has recently been addressed in some studies, cellular mechanisms underlying the long-term neurobiological and behavioral effects of opiate exposure during this critical period have still remained largely unexplored. Several reports have proposed that subtle long-lasting neurobiological alterations might be triggered by exposure to opiate derivatives or drugs of abuse particularly when this occurs during a critical phase of brain maturation such as adolescence. The present study was designed to investigate how chronic adolescent morphine exposure could affect the responsiveness of lateral paragigantocellular (LPGi) neurons to acute morphine administration in adult rats. Male Wistar rats received chronic escalating morphine or saline during adolescence (30-39d) for 10 days. During adulthood (65d), the extracellular unit activities of LPGi neurons were recorded in urethane-anesthetized animals. Results indicated that adolescent morphine treatment enhances the baseline activity of LPGi neurons. In addition, morphine-induced inhibition of spontaneous discharge rate was potentiated in adult rats received morphine during adolescence. However, this pretreatment did not affect the extent of morphine excitatory effect, onset or peak of cellular response and regularity of unit discharge in LPGi neurons. Our study supports the hypothesis that adolescent morphine exposure induces long-lasting neurophysiological alterations in brain regions known to play a role in mediating opiate effects. This finding sheds light on the possible effect of opiate pre-exposure on addiction susceptibility in future.

The role of orexin type-1 receptors in the development of morphine tolerance in locus coeruleus neurons: An electrophysiological perspective.

Long-term exposure to opioid agonists results in tolerance to their analgesic effects, so the effectiveness of opioid agonists in the management of pain becomes limited. The locus coeruleus (LC) nucleus has been involved in the development of tolerance to opiates. Orexin type-1 receptors (OX1Rs) are highly expressed in LC nucleus. Orexin plays a noteworthy role in the occurrence of morphine tolerance. The purpose of the present study is to investigate the role of orexin type-1 receptors in the development of morphine tolerance in LC neurons. In this study, adult male Wistar rats weighing 250-300g were utilized. Induction of morphine tolerance was obtained by single injection of morphine per day for 6 successive days. An orexin type-1 receptor antagonist (SB-334867) was injected into the lateral ventricle instantly prior to morphine injection. On day 7, the effect of morphine on the electrical activity of LC neurons was studied using in vivo extracellular single unit recording. The results demonstrate that morphine injection for 6 consecutive days led to the development of morphine-induced tolerance in LC neurons. In other words, there was a significant decrease in LC neuronal responsiveness to morphine injection. Inhibitory responses of LC neurons to intraperitoneally applied morphine can be observed with the treatment of the SB-334867 prior to morphine injection. This study showed that OX1R blockade by SB-334867 prevents the development of morphine tolerance in LC neurons. We hope that further studies will lead to considerable progress in understanding the molecular adaptations that contribute to morphine tolerance.

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

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 250-300 g were used in this study. To incite tolerance, morphine sulfate was injected intraperitonealy (10 mg/kg, i.p.) once a day for 6 days. A selective OXR1 antagonist (SB-334867) was microinjected into the right cerebral ventricle (10 µg/10 µl, i.c.v.) immediately before each morphine injection. On day 7, the effect of morphine (10 mg/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.