Neurochemical and molecular mechanisms underlying opioid dependence in the rat locus coeruleus

Resumen

Resumen: Dependence and tolerance to opiates have been extensively investigated. However, cellular and molecular process underliying these phenomenons are still unknown. It is known that hyperactivity of the pontine nucleus locus coeruleus (LC) cells, which is linked to opiate withdrawal, is due to a glutamate up-regulation. Opioid effects on the LC are mainly mediate by postsynaptic µ-opioid receptors (MORs). The mechanism responsible for the loss of functional MORs after chronic treatment with opioids has not yet been determined. The general aim of the present study was to characterize the modulation of glutamatergic system and MOR turnover in the rat LC. To achieve these objectives we used single-unit extracellular recording in brain slices and behavioural approaches in opioid-tolerant rats. On the one hand, our results show that excitatory amino acid transporters (EAAT) EAAT2 and EAAT3 are responsible for terminating glutamate action in the rat LC. The enhancement of the EAAT2 with ceftriaxone and the inhibition of the glutamate release by topiramate, prevent naltrexone-induced morphine-withdrawal behaviour and the development of glutamate receptors desensitization in the LC. On the other hand, our results suggest that MOR in the LC undergoes a rapid and constitutive turnover that depends on calcium- and activity-regulated trafficking from a cytoplasmatic pool of receptors; prolonged treatments with different opioid agonists induce marked changes in the kinetics of MOR turnover that prevent LC neurons from recovery to normal functionality. All together, this study provides further information about neurochemical and molecular events in the LC that account for the neuroplasticity accompanying prolonged administration of opioids: presynaptic glutamate release and uptake during opioid withdrawal and functional turnover and trafficking of MOR as an efficient process that is regulated by opioids. This better understanding of the neuroadaptive changes during chronic use of opiates may be relevant for improving the therapeutic benefits of opiates in the patient.