sympathectomy must somehow quiet the contralateral spread of spinal cord hyperexcitability underlying mirror-image pain

Blocking sympathetic function, whether by surgical sympathectomy, systemic phentolamine, or systemic guanethidine, relieves partial nerve injury-induced neuropathic pain in laboratory animal models as well as humans (8, 35, 146, 239, 278). Indeed, sympathectomy does not just relieve pathological pain in the body region ipsilateral to the CRPS-initiating event; rather, it also relieves pain arising from anatomically impossible mirror-image sites, that is, the identical body region contralateral to the initiating event (278). Thus sympathectomy must somehow quiet the contralateral spread of spinal cord hyperexcitability underlying mirror-image pain. 

Alterations in sympathetic fibers rapidly follow peripheral nerve injury. This occurs as sprouting of sympathetic fibers, creating aberrant communication pathways from the new sympathetic terminals to sensory neurons (35). Sympathetic sprouting has been documented in the region of peripheral terminal fields of sensory neurons (262), at the site of nerve trauma (57), and within the dorsal root ganglia (DRG) containing cell bodies of sensory neurons (248, 343). Each of these sites develops spontaneous activity and sensitivity for catecholamines and sympathetic activation (8, 53). 

The clearest evidence that immune activation participates in sympathetic sprouting comes from studies of the DRG. DRG cells receive signals that peripheral nerve injury has occurred via retrograde axonal transport from the trauma site. These retrogradely transported signals trigger sympathetic nerve sprouting into DRG (205, 308). As a result of nerve damage-induced retrogradely transported signals, glial cells within the DRG (called satellite cells) proliferate (248) and become activated (343); macrophages are recruited to the DRG as well (63, 176). In turn, the activated satellite glial cells (and, presumably, the macrophages) release proinflammatory cytokines and a variety of growth factors into the extracellular fluid of the DRG (206, 246 –248, 258, 277, 308, 358). These substances stimulate and direct the growth of sympathetic fibers, which form basket-like terminals around the satellite cells that, in turn, surround neuronal cell bodies (247, 248, 343). 

Until recently, the sympathetic sprouting, rather than the glial (satellite cell) activation, has attracted the attention of pain researchers. The satellite cells were ignored as they were thought to be irrelevant to the creation of exaggerated pain states. However, it may be speculated that the satellite cells, rather than the sympathetic sprouts, have the most impact on pain.

Physiol Rev • VOL 82 • OCTOBER 2002 • www.prv.org

Beyond Neurons: Evidence That Immune and Glial Cells 

Contribute to Pathological Pain States 

LINDA R. WATKINS AND STEVEN F. MAIER 

Department of Psychology and the Center for Neuroscience, 

University of Colorado at Boulder, Boulder, Colorado 

Chronic pain can occur after peripheral nerve injury, infection, or inflammation

Chronic pain can occur after peripheral nerve injury, infection, or inflammation. Under such neuropathic pain conditions, sensory processing in the affected body region becomes grossly abnormal. Despite decades of research, currently available drugs largely fail to control such pain. This review explores the possibility that the reason for this failure lies in the fact that such drugs were designed to target neurons rather than immune or glial cells. It describes how immune cells are a natural and inextricable part of skin, peripheral nerves, dorsal root ganglia, and spinal cord. It then examines how immune and glial activation may participate in the etiology and symptomatology of diverse pathological pain states in both humans and laboratory animals. Of the variety of substances released by activated immune and glial cells, 

proinflammatory cytokines (tumor necrosis factor, interleukin-1, interleukin-6) appear to be of special importance in the creation of peripheral nerve and neuronal hyperexcitability.

Although this review focuses on immune modulation of pain, the implications are pervasive. Indeed, all nerves and neurons regardless of modality or function are likely affected by immune and glial activation in the ways described for pain.

Physiol Rev   82: 981–1011, 2002; 10.1152/physrev.00011.2002. 

may be relevant to the pathogenesis of human dysautonomias

1. Systemic injection of monoclonal antibodies to neural acetylcholinesterase in adult rats caused a syndrome with permanent, complement-mediated destruction of presynaptic fibers in sympathetic ganglia and adrenal medulla. Ptosis, hypotension, bradycardia, and postural syncope ensued. In sympathetic ganglia, acetylcholinesterase activity disappeared from neuropil but not from nerve cell bodies. Choline acetyltransferase activity and ultrastructurally defined synapses were also lost. Electrical stimulation of presynaptic fibers to the superior cervical ganglion ceased to evoke end-organ responses. On the other hand, direct ganglionic stimulation remained effective, and the postganglionic adrenergic system appeared intact. Motor performance and the choline acetyltransferase content of skeletal muscle were preserved, as was parasympathetic (vagal) function. This model of selective cholinergic autoimmunity represents another tool for autonomic physiology and may be relevant to the pathogenesis of human dysautonomias.
2. http://www.jstor.org/pss/2356466