Are δ-Opioid Receptors Involved in Deep Brain Stimulation?

Abstract

Despite its widespread use, the underlying mechanism of deep brain stimulation (DBS) remains unknown. Once thought to impart a “functional inactivation”, there is now increasing evidence showing that DBS actually can both inhibit neurons and activate axons, generating a wide range of effects. This implies that the mechanisms that underlie DBS work not only locally but also at the network level. Therefore, not only may DBS induce membrane or synaptic plastic changes in neurons over a wide network, but it may also trigger cellular and molecular changes in other cells, especially astrocytes, where together the glial-neuronal interactions may explain effects that are not clearly rationalized by simple activation/inhibition theories alone. Recent studies suggest that (1) High frequency stimulation (HFS) activates astrocytes and leads to the release of gliotransmitters that can regulate surrounding neurons at the synapse; (2) Activated astrocytes modulate synaptic activity and increase axonal activation; (3) Activated astrocytes can signal further astrocytes across large networks, contributing to observed network effects induced by DBS; (4) Activated astrocytes can help explain the disparate effects of activation and inhibition induced by HFS at different sites; and (5) Astrocytes contribute to synaptic plasticity through long-term potentiation (LTP) and depression (LTD), possibly helping to mediate the long term effects of DBS. More recently, we found that δ-Opioid receptor (DOR) activation reduces α-synuclein overexpression and oligomer formation, thus attenuating cellular injury after MPP+ exposure. Indeed, DOR activation protects both glial and neuronal cells against injury in our in-vitro studies. Furthermore, we demonstrate that PD pathophysiology is critically attributed to DOR impairment in the brain of a mouse PD model. Moreover, recent evidence suggests that DOR activation promotes the release of dopamine in the striatum. Since we have previously shown that brain stimulation increased the release of encephalin, an endogenous DOR agonist, in the brain, the mechanism of DBS may be, at least partially, attributed to DOR activity that confers protection in both neurons and astrocytes. Together, the plastic changes in these glial-neuronal interactions network-wide likely underlie the range of effects seen, from the variable temporal latencies to observed effect to global activation patterns. This chapter provides a broad review of our understanding of DBS mechanisms, and then presents recent research progress in the literature on how astrocytes play a key role in DBS efficacy and our novel observations on a potential DOR mechanism for DBS.