"Neuronal Mechanisms Underlying Opioid Addiction"

The nucleus paragiagantocellularis (PGi)/locus coeruleus (LC) pathway has been shown to play a role in opioid dependence and withdrawal. Using a multiple-electrode recording technique, we found a novel effect of morphine on the firing pattern of LC neurons. Our data show that morphine induces long-lasting synchronous oscillatory burst activities in the LC in addition to its well-known inhibitory action (Zhu and Zhou, J Neurosci, 2001). As a result of synchronized LC firing, morphine can facilitate neurotransmitter norepinephrine (NE) release in LC target areas. NE is an important neuromodulator that has been shown to induce neural plasticity in several brain regions. We have demonstrated that NE is involved in morphine-induced long-lasting potentiation in the hippocampal dentate gyrus, which is one of the LC target areas (Zhu and Zhou, Eur J Pharm, 2003). Thus, the morphine-induced synchronous activity in the LC could be an important neuronal signal that induces neural plasticity leading to opioid addiction. Understanding the mechanisms underlying the morphine-induced LC synchrony will provide insight into understanding of opioid addiction. Our recent findings suggested that excitatory amino acid (EAA) inputs to the LC contribute to the morphine-induced LC synchrony (Zhu et al., SFN, 2003). Since the PGi provides the major EAA input to the LC, it is possible that opioid-induced changes in PGi neuronal activity drive the LC synchrony. In the present application, we will test this hypothesis by studying opioids’ action on the temporal relationships among the activities of PGi neurons. A unique strength of this application is that we employ the multiple-electrode extracellular recording technique that allows us to record several PGi neurons simultaneously and to study their temporal relationships, i.e., synchronized firing. Aim 1 is to examine whether a single dose of opioid drugs induces synchronous burst activities in the PGi in opioid-naïve rats. Aim 2 is to examine whether opioid-induced changes in PGi neuronal activity affects the synchronous oscillatory discharges in the LC. Aim 3 is to identify the adaptive changes in firing patterns of the PGi during the development of opioid dependence and during the withdrawal from chronic opioid treatment.