Activated Glia: Targets for the Treatment of Neuropathic Pain
The workshop was organized by Mark S. Cooper, PhD (Univ. Washington); Donald C. Manning, MD, PhD (Shionogi USA, Inc.); and Kirk W. Johnson, PhD (MediciNova, Inc.). Additional information about the workshop, including a video of microglial activation from Michael Dailey (U. Iowa), is available on the workshop website at www.rsds.org/3/research/glia_workshop.
On October 8-9, 2010, a workshop in Chicago considered the role of activated glia in the neural mechanisms of chronic pain. The workshop, Activated Glia: Targets for the Treatment of Neuropathic Pain, was sponsored by the Reflex Sympathetic Dystrophy Syndrome Association (RSDSA; www.rsds.org) and included clinicians, scientists, patient advocates, and industry representatives interested in the study and treatment of painful conditions. RSDSA is a not-for-profit organization that promotes awareness, provides access to resources, funds research, and gives support and information to people who suffer Complex Regional Pain Syndrome (CRPS). Although RSDSA’s primary interest concerns CRPS, topics of the workshop pertained to other neuroinflammatory conditions, including Huntington’s disease, fibromyalgia, spasmodic torticollis, and multiple sclerosis.
There is a growing body of science to persuade us to think of disparate neurologic, neuro-muscular and myofascial syndromes as a single class of diseases characterized by neuroinflammation. Clinicians have long known that there are central nervous system abnormalities in people who suffer chronic pain. In a bygone era, they thought that premorbid personality and characterologic predispositions were responsible for a broad range of behaviors associated with chronic pain. We now understand that “central sensitization”1 is responsible for many of the sensory, mood and movement disorders observed in a variety of neuroinflammatory diseases. There is good reason to think that activated glia mediate such disorders and play a significant role in the onset and course of neuroinflammation and neurodegeneration that exacerbate nociception and the experience of pain.
There is a rich literature on the science of glia and how many diseases are caused and exacerbated by the activation of glia, however, much of this literature is unfamiliar to physicians and their patients. Yet, glia constitute 50% of the volume of our central nervous system (CNS).2 The collected human nervous systems—central, peripheral and autonomic—could not function without them. While there are about 50 billion neurons in the CNS, glia in the CNS outnumber neurons 10:1.3 In other words, 90% of cells in the CNS, or half a trillion of them, are glia.
“Glia” refers to a diverse set of specialized cell types that are found both in the peripheral nervous system (Schwann cells, satellite glia, perineural glia) and in the central nervous system (astrocytes, oligodendrocytes, microglia, and perivascular glia).4 Glia are also genetically and immunologically active, and their up- or down-regulation has broad effects on neurons and neuronal pathways. The state of the science of glial activation, its role in the experience of pain, and its implication for potential treatment of chronic pain was the subject of this Chicago workshop.
For this discussion, we define “pain” as the experience of the neural representation of the transduction, transmission, encoding and storage of actual or simulated tissue damage.5 The simulation may be either peripheral, as in the subcutaneous injection of capsaicin, or central, as in the stimulation of central projecting spinal pathways or cortical somatic maps. “Good pain,” derived from the definitions of Lippe, is an experience that does not last long and enhances the quality of life by being corrective, instructive and adaptive.6 Lippe’s “bad pain,” on the other hand, is an experience of suffering that degrades the quality of life. Such is the pain of CRPS, diabetic polyneuropathy and fibromyalgia, among many other diseases. From a clinical perspective, the role of activated glia in “bad pain,” such as neuropathic or neuroinflammatory pain, is currently hypothetical but probably will not be so for long.
We can divide the Chicago workshop presentations into four general subjects:
A. The clinical diagnosis and course of neuropathic pain, particularly CRPS,
B. The science of glia and their activation,
C. The detection of activated glia, and
D. Possible targets for pain treatment based on the science of activated glia.
As we discuss each group of presentations, the reader will easily consider the implications of the knowledge they contain to the original and remarkably prescient description of CRPS by Silas Weir Mitchell (1829-1914), an American Civil War neurologist. In 1872, Dr. Silas Weir Mitchell published a neurological text entitled: Injuries of Nerves and Their Consequences.7 Mitchell described an intense burning pain in soldiers who had suffered nerve injuries:
“Long after every other trace of the effects of a wound has gone, these neuralgic symptoms are apt to linger, and too many carry [with] them throughout the long years this final reminder of the battlefield.”
One of Dr. Mitchell’s patients, David Schievely (age 17), was wounded in the Battle of Gettysburg on July 2, 1863, when a bullet shattered his right clavicle and exited the posterior part of his right arm. Six months after the battle, Mitchell writes:
“…The burning in the right hand is intense and constant….Both hands are kept covered with loose cotton gloves, which he wets at brief intervals. He is especially fearful of having the right hand touched; is nervous and hysterical to such a degree that his relatives suppose him to be partially insane. It is difficult to even examine him properly on account of his timidity, and his whole appearance exhibits the effects of pain…”
Mitchell expressed his belief that this unbearable burning pain, which he termed causalgia, was caused by a combination of (a) inflammation within the injured nerve, (b) physiological changes in the terminals of nerves, and (c) abnormal actions originating from the spinal cord.7 Current knowledge about glia cell activation in the injured nerve, as well as in the spinal cord, appears to validate Mitchell’s insights.
The Chicago Workshop: Activated Glia and Neuropathic Pain
Donald Manning (Shionogi, USA) opened the program by declaring “Knowledge defines our possibilities, but philosophy (disease concept) defines our goals.” He further stated that a paradigm shift is currently in progress and which will lead us away from understanding pain in terms of neuronal function only.8,9 A neuronal model of CRPS does not work. The “non-anatomic” features of CRPS symptoms and signs are not adequately explained by a neuronal, somatotopic model alone, and this error leads clinicians to the false conclusion that the signs and symptoms are “non-organic” and psychogenic. The same can be said for fibromyalgia and other diseases.