Invited minireviewImmune-to-brain communication dynamically modulates pain: Physiological and pathological consequences
Introduction
While acute pain is a normal, physiological, and adaptive response to noxious stimuli, chronic pain is a maladaptive, pathological condition. Chronic pain in people fails, by-and-large, to be controlled by currently available drugs. An effective drug for human chronic pain is one that provides only partial relief for one out of five patients, while the remaining four patients experience no relief from pain (McQuay et al., 1995, McQuay et al., 1996). Why these drugs fail is an enigma, but may be due to the fact that all of the currently available drugs target neurons. The present review examines why targeting neurons may not be an optimal strategy for treating this debilitating condition. Furthermore, it proposes that basic principles of neuroimmunology may provide novel approaches for resolving the immense human suffering caused by chronic pain.
Classically, the pain pathway has been conceived of as a chain of neurons from periphery to cerebral cortex, in which one neuron relays pain information to the next neuron in line, and so on. Decades of research have clearly shown that pain transmission along this neuronal path can be modulated by pain suppressive and pain enhancing circuitry, again comprising neurons. In the past few years, it has become clear that non-neuronal cells of the central nervous system (CNS) also play pivotal roles in pain facilitation and can result in hot, cold, and hard pressure pains being grossly amplified and even warm, cool, and light touch being perceived as pain. These key nonneuronal players in pain are glia; specifically, activated microglia and astrocytes. These are immunocompetent cells of the CNS. As such, they are activated by classical immune stimuli such as viruses, bacteria, and trauma. However, they are also now known to be activated by substances released by neurons within the spinal cord. These spinal neuronal signals are released in response to inflammation and damage in the body, conditions which lead to both glial activation and glially driven pain facilitation (see Fig. 1).
The thesis of this review is that glia act as a “volume control” for pain. As will be discussed below, glia are not involved in normal, everyday pain. But they are critically involved in pain enhancement. When glia become activated, they amplify pain by amplifying the messages relayed by sensory nerves to the spinal cord, and by amplifying the spinal pain message relayed to the brain.
This review will be organized in a series of sections, beginning with a brief overview of normal and abnormal pain processing. This will be followed by a discussion of how the study of immune-to-brain communication helped lead to the realization that spinal cord glia can powerfully modulate pain, both physiologically (e.g., as part of the sickness response) and pathologically (e.g., in response to peripheral inflammation and trauma).
Section snippets
Pain is normally adaptive and dynamic
The sensation of pain normally serves to protect the organism from harm, triggering immediate behavioral responses to prevent, or at least minimize, tissue damage. In addition, pain is a powerful motivator for learning about dangers and how to avoid them. Painful stimuli, such as acids, heat, cold, and hard pressure, activate specific receptors expressed on nerve endings. These receptors are expressed only by a select sub-population of peripheral nerves, called A-delta and C fibers, which are
Pain processing can become pathological
Normally, pain is experienced as an acute event. When the pain continues well after an injury has healed, such pain is no longer adaptive. It is at this point that pain is called pathological. Under such conditions, pain becomes grossly amplified to a point at which even warm, cool, and light touch are now perceived as painful. Thus, for example, chronic pain patients find clothing or bedsheets unbearable when these come in contact with the affected area. Body regions beyond the site of damage
Historical overview: sickness, proinflammatory cytokines, and pain
While a number of presumed neuronally released neuromodulators, like nitric oxide and prostaglandins, have long been implicated in spinally mediated pain facilitation, substances released from activated glia, such as proinflammatory cytokines, have not. This is because glia have not been classically thought to regulate neuronal function. Only recently has it become clear that glia are able to significantly influence neuronal activity (reviewed in Araque et al., 1999). Indeed, neuronal synapses
Glia: immunocompetent cells of the CNS
As used here, the term “glia” refers to both microglia and astrocytes. These two cell types are very similar in terms of the stimuli that activate them, and both are activated by conditions that induce pain facilitation. When activated, each can further activate the other, leading to the release of a variety of neuroexcitatory products. Many of these products of activated microglia and astrocytes can enhance pain transmission in the spinal cord dorsal horns.
Before proceeding to a discussion of
Sciatic inflammatory neuropathy: hyperalgesia and glial activation
As already noted, hyperalgesia can be viewed as a component of the sickness response that results from peripheral immune activation. The immune-to-brain communication that initiates sickness employs both blood-borne and neural routes, with the vagus nerve having been shown to carry the peripheral nerve part of the “message”(Watkins and Maier, 1999). These immune-to-brain communication pathways induce the production of proinflammatory cytokines in the brain and spinal cord, whereby spinal
Linkage between spinal proinflammatory cytokines and hyperalgesia
In response to specific neuronal signals activated glia can release the proinflammatory cytokines, tumor necrosis factor (TNF), interleukin-1 (IL1), and interleukin-6 (IL6). Proinflammatory cytokines do not appear to be constitutively released in the spinal cord, at least to any degree that alters pain processing. Similar to results with the glial inhibitors, pharmacological blockade of the activity of proinflammatory cytokines does not interfere with normal acute pain (Milligan et al., 2003).
Glia and mirror image pain
It may be recalled that mirror image pain is a form of hyperalgesia that is perceived to arise from the healthy, opposite side of the body relative to the original injury site. As noted above, mirror image pain is observed in the SIN model of neuropathic pain following intense peri-sciatic inflammation. In addition, mirror image pain is observed following frank nerve trauma induced by CCI (Paulson et al., 2000). In CCI, the sciatic nerve is loosely ligated with immunogenic sutures at mid-thigh
Summary and conclusions
Sickness responses include a broad constellation of adaptive changes that occur in response to immune challenge. Pain enhancement (hyperalgesia) is just one component of this survival-oriented response. It, like many more classical sickness responses, was discovered to be mediated by glial activation and release of proinflammatory cytokines. This was a novel and surprising finding from the perspective of the pain field, which had assumed that glia had no role in pain. This new view of glial
Acknowledgments
This work is supported by AI51093, DA15642, NS40696, NS38020, and DA015656.
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