Norman Cousins Lecture
Glia as the “bad guys”: Implications for improving clinical pain control and the clinical utility of opioids

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Abstract

Within the past decade, there has been increasing recognition that glia are far more than simply “housekeepers” for neurons. This review explores two recently recognized roles of glia (microglia and astrocytes) in: (a) creating and maintaining enhanced pain states such as neuropathic pain, and (b) compromising the efficacy of morphine and other opioids for pain control. While glia have little-to-no role in pain under basal conditions, pain is amplified when glia become activated, inducing the release of proinflammatory products, especially proinflammatory cytokines. How glia are triggered to become activated is a key issue, and appears to involve a number of neuron-to-glia signals including neuronal chemokines, neurotransmitters, and substances released by damaged, dying and dead neurons. In addition, glia become increasingly activated in response to repeated administration of opioids. Products of activated glia increase neuronal excitability via numerous mechanisms, including direct receptor-mediated actions, upregulation of excitatory amino acid receptor function, downregulation of GABA receptor function, and so on. These downstream effects of glial activation amplify pain, suppress acute opioid analgesia, contribute to the apparent loss of opioid analgesia upon repeated opioid administration (tolerance), and contribute to the development of opioid dependence. The potential implications of such glial regulation of pain and opioid actions are vast, suggestive that targeting glia and their proinflammatory products may provide a novel and effective therapy for controlling clinical pain syndromes and increasing the clinical utility of analgesic drugs.

Section snippets

Overview

Within just the past decade, there has been increasing recognition that glia are far more than simply “housekeepers” for neurons, providing neurochemical precursors and energy sources to neurons, regulating extracellular ion concentrations, removing debris, and so on. It is now known that glia also importantly contribute to fever, alterations in sleep, disruption of learning and memory, as well as to neuroinflammatory/neurodegenerative conditions such as ischemia/stroke, Alzheimer’s disease,

Glia

The work to be reviewed focuses on two types of glial cells, astrocytes and microglia. When these cells become activated, they (a) upregulate cell-type specific activation markers (allowing this reflection of activation to be easily visualized using immunohistochemistry) and (b) release a variety of substances (e.g., proinflammatory cytokines, chemokines, ATP, excitatory amino acids, nitric oxide, etc.) that enhance pain by increasing the excitability of nearby neurons. Microglia and astrocytes

Glial dysregulation of pain

Under normal situations, when spinal glia are in their basal state, they have little-to-no influence on pain responsivity (Fig. 1). Various drugs that suppress glial function have consistently failed to alter responsivity to heat or mechanical stimuli in normal animals (Hashizume et al., 2000, Ledeboer et al., 2005, Meller et al., 1994). While data from knockouts reveal reductions in basal pain responsivity in adult mice with disrupted IL-1 signaling, these changes appear related to

How do spinal glia “know” to become activated?

A key question is: “What is released in spinal cord, as a result of inflammation/trauma in the periphery that “tells” glia to activate?” Increasing focus is being directed at microglia as the “trigger”, as the initiator of pain facilitation. Microglia are exquisitely sensitive to signals of “not self” or “not normal”, leading them to be far more reactive in responding to CNS challenges than other candidate cell types (Kreutzberg, 1996). Similarly, spinal cord microglia are the earliest glial

How can glial activation affect neuronal activity?

It is remarkable that diverse enhanced pain states are all suppressed by inhibiting glial function (Watkins and Maier, 2003). However, this does not provide insight into what the glial products are that enhance pain. This issue is, in part, relatively simple and, in part, complicated. “Relatively simple” refers to situations in which pain enhancement can be clearly linked to the release of classical glial products, such as proinflammatory cytokines. “Relatively” simple must be kept in mind

Non-neuronal cells beyond glia: might they also contribute to pain enhancement?

Before leaving the topic of pain facilitation, it is worth noting that astrocytes and microglia may well not be the only non-neuronal cell types capable of enhancing pain in spinal cord. As noted above (Section 2), other cell types in spinal cord can generate proinflammatory cytokines and other neuroexcitatory substances, such as fibroblasts, perivascular macrophages, dendritic cells, and endothelial cells. The potential involvement of such cells in pain facilitation has not yet been explored.

Responses of glia to chronic opioids: contribution to morphine tolerance and withdrawal-induced pain enhancement

A strong case has been made that the mechanisms underlying neuropathic pain and morphine tolerance are strikingly similar (Mayer et al., 1999). Given the strength of evidence implicating glia in pain facilitation, including neuropathic pain, it was natural to extend this question to whether glia were similarly involved in the production of morphine tolerance. As will be reviewed below, it is now clear that this is indeed the case (Watkins et al., 2005).

The first report linking glia to morphine

How can glial activation affect neuronal responses to opioids?

This issue is obviously related to the parallel discussion in Section 5, above. As we have shown that proinflammatory cytokines are also released in response to morphine (Johnston et al., 2004) the reader is referred back to the prior section for review of issues that are equally pertinent here. Beyond what has already been discussed, there are additional mechanisms that may come into play when exploring how glial activation may suppress responsivity to morphine.

The first is that opioids can

Implications for clinical pain control

The potential implications of glial involvement in the dysregulation of pain and opioid actions are vast. Regarding pain, the fundamental, inescapable fact is that present treatments for chronic pain fail. The drugs currently used to treat clinical pain problems were all developed to target neurons, prior to the discovery that glia regulate pain. Present knowledge of glial regulation of pain derives from many different laboratories using many different animal and in vitro models, and equally as

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    Linda R. Watkins was the recipient of the 2006 Norman Cousins Award.

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