Norman Cousins Lecture. Glia as the "bad guys": implications for improving clinical pain control and the clinical utility of opioids

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.

Figures

Figure 1

Classical and non-classical views of pain transmission and pain modulation. Panel (a). Classical pain transmission pathway. When a noxious (painful) stimulus is encountered, such as stepping on a nail as shown, peripheral “pain”-responsive A-delta and C nerve fibers are excited. These axons relay action potentials to the spinal cord dorsal horn. Here, neurotransmitters are released by the sensory neuron and these chemicals bind to and activate postsynaptic receptors on pain transmission neurons (PTNs) whose cell bodies reside in the dorsal horn. Axons of the PTNs then ascend to the brain, carrying information about the noxious event to higher centers. The synapse interconnecting the peripheral sensory neuron and the dorsal horn PTN is shown in detail in panels (b) and (c).Panel (b): Normal pain. Under basal conditions, pain is not modulated by glia. Under these circumstances, glia are quiescent, and thus not releasing pain modulatory levels of neuroexcitatory substances. Information about noxious stimuli arrives from the periphery along A-delta and C fibers, causing the release of substance P and excitatory amino acids (EAAs) in amounts appropriate to the intensity and duration of the initiating noxious stimulus. Activation of neurokinin-1 (NK-1) receptors by substance P and activation of AMPA receptors by EAAs cause transient depolarization of the PTNs, thereby generating action potentials that are relayed to brain. NMDA-linked channels are silent as they are chronically “plugged” by magnesium ions. Panel (c) Pain facilitation: classical view. In response to intense and/or prolonged barrages of incoming “pain” signals, the PTNs become sensitized and over-respond to subsequent incoming signals The intense and/or prolonged barrage depolarizes the PTNs such that the magnesium ions exit the NMDA-linked channel. The resultant influx of calcium ion activates constitutively expressed nitric oxide synthase (cNOS), causing conversion of L-arginine to nitric oxide (NO). Because it is a gas, NO rapidly diffuses out of the PTNs. This NO acts presynaptically to cause exaggerated release of substance P and EAAs. Postsynaptically, NO causes the PTNs to become hyperexcitable. Glia have not been considered to have a role in creating pain facilitation in this neuronally driven model. Panel (d): Pain facilitation: new view. Here, glial activation is conceptualized as a driving force for creating and maintaining pain facilitation. The role of glia is superimposed on the NMDA-NO-driven neuronal changes detailed in (c), so only the aspects added by including glia in the model are described here. Glia are activated (shown as hypertrophied relative to (b), as this reflects the remarkable anatomical changes that these cells undergo on activation) by three sources: bacteria and viruses which bind specific activation receptors expressed by microglia and astrocytes; substance P, EAAs, fractalkine, and ATP released by A-delta and/or C fiber presynaptic terminals (shown here) or by brain-to-spinal cord pain enhancement pathways (not shown); and NO, prostaglandins (PGs) and fractalkine released from PTNs. Following activation, microglia and astrocytes cause PTN hyperexcitability and the exaggerated release of substance P and EAAs from presynaptic terminals. These changes are created by the glial release of NO, EAAs, reactive oxygen species (ROS), PGs, proinflammatory cytokines (for example, IL1, IL6 or TNF), and nerve growth factor. Modified by Journal of Internal Medicine with permission, from Trends in Neuroscience.

Figure 2

Summary of neuronal signals binding to microglial receptors leading to microglial activation and associated with pain facilitation. Neurons release these signals following specific stimulation or as a consequence of neuronal damage. As described in the main text, these receptors and signals have been associated with chronic pain states. Receptors are presented in bold. Neuronal signals bind chemokine receptors (Fractalkine [FKN] binds CX3CR1; CCL2 binds CCR2; IP-10 [interferon-inducible protein] and CCL21 [secondary lymphoid tissue chemokines] bind CXCR3); toll-like receptors (high mobility group box 1 [HMGB1] binds Toll Like Receptors 2 and 4 [TLR2 and TLR 4] and proteoglycans, heat shock proteins [HSPs], saturated fatty acids, and cations bind TLR4); and lysophosphatidic acid binds LPA1. Classical pain neurotransmitters are released by neurons and act on specific microglial receptors such as adenosine triphosphate (ATP) binding P2X4; Substance P binding NK-1; and excitatory amino acids [EAA] binding NMDA and AMPA receptors.

FIGURE 3

A: The classical view of opioid analgesia proposes (-)-opioid agonist isomers stereoselectively bind to classical opioid receptors producing an inhibitory influence on nociceptive signal transmission. B: A growing body of literature suggests that the classical view of analgesia ignores an important nociceptive modulatory influence driven by opioid induced glial activation resulting from opioid agonists binding to glial opioid binding receptors which in turn increase proinflammatory cytokine (such as interleukin-1) expression & release leading to a decrease in opioid efficacy at the neuronal component. C: (-)-Opioid antagonists bind to both the neuronal & glial components resulting in blockade of any potential opioid analgesia & glial activation. D: Due to the stereoselectivity of neuronal opioid receptors only the (-)-isomer of opioid agonists & antagonists are able to bind. Therefore, when a combination of an opioid (+)-antagonist & an opioid (-)-agonist are introduced to this system, the (+)-antagonist is unable to bind to the stereoselective neuronal opioid receptor, but is able to block the non-stereoselective glial site. The opioid (-)-agonist can act freely at the neuronal opioid receptor, but is unable to bind to the glial site due to its blockade by the (+)-antagonist. Therefore, this situation produces opioid receptor mediated analgesia without the opposing force of opioid induced glial activation, thereby potentiating opioid analgesia. E: Based on the above hypothesized series of events this schematic diagram demonstrates how analgesia decreases over time as a direct result of increased glial activation.