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Home > > Science Meeting Summaries & Special Reports > Frontiers in Addiction Research > Glial Cells and Addiction


Header - Frontiers in Addiction Research

GLIAL CELLS AND ADDICTION

Co-Chairs:

Diane Lawrence, Ph.D.
National Institute on Drug Abuse

David Thomas, Ph.D.
National Institute on Drug Abuse

Da-Yu Wu, Ph.D.
National Institute on Drug Abuse

Overview

Glial cells play significant roles in neural development, plasticity, neurorepair, and pain modulation, but little is known about how glial cell function is affected by substance abuse. This symposium provides an understanding of the complex nature of astrocyte function and microglial activation; highlights new findings on glial modulation of neuroplasticity, neurotoxicity, and pain; and explores potential ways that substance abuse can affect these processes.

Glia as the “Bad Guys” in Dysregulating Pain & Opioid Actions: Implications for Improving Clinical Pain Control
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Glia as the “Bad Guys” in Dysregulating Pain & Opioid Actions: Implications for Improving Clinical Pain Control
Linda R. Watkins, Ph.D.

Work during the past 15 years has challenged classical views of pain and opioid actions. Glia (microglia and astrocytes) in the central nervous system are now recognized as key players in pain amplification, including pathological pain such as neuropathic pain; compromising the ability of opioids, such as morphine, for suppressing pain; causing chronic morphine to lose effect, contributing to opioid tolerance; driving morphine dependence/withdrawal; and driving morphine reward, linked to drug craving and drug abuse. These opioid effects on glia are caused by the activation of a non-classical, non-stereoselective opioid receptor that is distinct from the receptor expressed by neurons that suppresses pain. This implies that the effects of opioids on glia and neurons should be pharmacologically separable. Our studies have revealed that opioid administration leads to an opposing process: glial release of proinflammatory cytokines that oppose the analgesic actions of opioids. The glial opposition of analgesia occurs in response to a broad range of opioids, including, but not restricted to, morphine and methadone. Upon opioid administration, both pain suppression and proinflammatory cytokine-induced pain enhancement simultaneously occur as opponent processes. Blocking proinflammatory cytokine actions markedly enhances the magnitude and duration of opioid analgesia. Indeed, morphine dose-response functions performed in the absence versus presence of cytokine inhibitors reveal a marked leftward shift in the dose-response function when proinflammatory cytokine actions are blocked, demonstrating that these endogenous proinflammatory mediators naturally compromise the analgesic efficacy of both intrathecally and systemically delivered opioid analgesics. Glial proinflammatory cytokines upregulate in response to chronic opioids, contributing to the development of opioid tolerance, opioid dependence/withdrawal, and opioid reward, measured both neurochemically (via in vivo microdialysis) and behaviorally (via conditioned place preference). Of fundamental importance is our discovery that opioids activate glia via a non-stereoselective receptor separate from the classical opioid receptor: toll-like receptor 4 (TLR4). Given that neuronally inactive (+)-naloxone blocks this glial receptor, but not neuronal opioid receptors, this finding predicts that (+)-opioids such as (+)-naloxone should potentiate opioid analgesia by not blocking morphine effects on neurons, yet removing glial activation that opposes analgesia. This is true.

On the basis of our data, we predict that suppressing glial activation will suppress the pathological pain of various etiologies, improve opioid analgesia, suppress opioid tolerance, suppress opioid dependence, and suppress opioid reward linked to drug craving/drug seeking.

Further, our data lead us to conclude that opioid activation of glia is fundamentally different than for neurons: glial receptors are not stereoselective, opioid effects on glia must be via different receptors (TLR4) than for neurons, effects of glia and neurons should be separable, and to increase the efficacy of opioids, one should either modify opioids so they do not bind glia and/or create long-lasting, orally available versions of [+]-naloxone.

Astrocytic Modulation of Neuronal Excitability in the Nucleus Accumbens
Philip G. Haydon, M.D.

[Slides not available]

For the past decade, we have begun to appreciate that astrocytes can play active signaling roles in the nervous system. These glial cells express a plethora of neurotransmitter receptors that can mobilize intracellular Ca2+. In response to Ca2+ elevations, astrocytes release chemical transmitters, including glutamate, adenosine triphosphate, and D-serine, that act on neighboring neurons to modulate synaptic transmission and neuronal excitability. Because astrocytes are known to express mGluR5, a receptor that is critical for cocaine-induced drug-seeking behaviors, we have asked whether this receptor modulates neuron function through a glial intermediate. Studies in the nucleus accumbens demonstrate that activation of mGluR5 stimulates astrocytic Ca2+ oscillations, and that as a consequence, astrocytes excite medium spiny neurons (MSNs) through the glial release of glutamate. Furthermore, brief stimulation of glutamatergic afferents induces prolonged excitation of astrocytes, which in turn are able to continuously excite MSNs. We summarize these results and discuss the diversity of actions of glial-induced transmission and how it can impact synaptic transmission and neural network function.

Fine-Tuning Microglial Activation Toward Neuroprotection or Cytodestruction: The Role of Microglial Heterogeneity and Novel Receptor Families
Monica J. Carson, Ph.D.

[Slides not available]

Microglia are the tissue macrophages of the central nervous system (CNS), and their activation is a frequent and early response in nearly all CNS neuropathologies. Similar to other macrophage populations, microglia are highly plastic in their phenotype and are capable of performing a wide variety of cytoprotective (“wound healing”) versus cytodestructive (pathogen-defense) functions.

To date, there is substantial debate as to which specific microglial responses that occur during neurodegenerative disease are beneficial versus maladaptive for CNS function. In part, this debate is limited by the incomplete knowledge of how the CNS environment elicits and directs microglia activation. Using flow cytometry and in situ hybridization analysis of murine models of immune- and non-immune-mediated neurodegeneration, we contrast microglial expression of Golli-myelin basic protein and two related receptor families: triggering receptors expressed on myeloid cells (TREMs) and TREM-like transcripts (TLTs). Because of the presence of immunoreceptor tyrosine-based inhibitory motif domain, TLTs are postulated to trigger inhibitory intracellular signaling pathways, whereas TREMs are postulated to trigger immunoreceptor tyrosine-based activation motif-mediated activating intracellular signaling pathways. The heterogeneous basal and induced expression of these molecules suggests that microglia function is heterogeneous in the CNS and highly context-dependent.

Using overexpression and knock-down strategies, we demonstrated the broad array of microglial functions regulated by these receptor families. We further found that despite being defined as “activating” receptors, TREMs may help to trigger neuroprotective and anti-inflammatory responses within the CNS.

Glial Cell Induction and Suppression of Neuronal Synapses
Ben A. Barres, M.D., Ph.D.

[Slides not available]

We previously identified thrombospondin (TSP) as a 450-kD astrocyte-secreted protein that is sufficient to induce structural central nervous system (CNS) synapses, and is necessary for astrocyte-enhanced synaptogenesis in vitro. In order to better understand the molecular and cellular mechanisms by which TSP promotes the formation of structural synapses, we investigated the identity of the responsible TSP receptor(s). We found that all five TSP isoforms have strong synapse-inducing activity as a result of sharing a common epidermal growth factor-like domain. Using this domain, we have identified that TSP induces synapse formation through a novel interaction with a widely expressed transmembrane neuronal cell surface molecule, which has not been previously linked to synapse formation. The identification of the mechanism by which TSP induces synapse formation will hopefully shed light on CNS synapse formation and the role of astrocytes in CNS development, addiction, and disease.


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