Abstract
Intractable neuropathic pain is a frequent consequence of nerve injury or disease. When peripheral nerves are injured, damaged axons undergo Wallerian degeneration. Schwann cells, mast cells, fibroblasts, keratinocytes and epithelial cells are activated leading to the generation of an “inflammatory soup” containing cytokines, chemokines and growth factors. These primary mediators sensitize sensory nerve endings, attract macrophages, neutrophils and lymphocytes, alter gene expression, promote post-translational modification of proteins, and alter ion channel function in primary afferent neurons. This leads to increased excitability and spontaneous activity and the generation of secondary mediators including colony stimulating factor 1 (CSF-1), chemokine C-C motif ligand 21 (CCL-21), Wnt3a, and Wnt5a. Release of these mediators from primary afferent neurons alters the properties of spinal microglial cells causing them to release tertiary mediators, in many situations via ATP-dependent mechanisms. Tertiary mediators such as BDNF, tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β), and other Wnt ligands facilitate the generation and transmission of nociceptive information by increasing excitatory glutamatergic transmission and attenuating inhibitory GABA and glycinergic transmission in the spinal dorsal horn. This review focusses on activation of microglia by secondary mediators, release of tertiary mediators from microglia and a description of their actions in the spinal dorsal horn. Attention is drawn to the substantial differences in the precise roles of various mediators in males compared to females. At least 25 different mediators have been identified but the similarity of their actions at sensory nerve endings, in the dorsal root ganglia and in the spinal cord means there is considerable redundancy in the available mechanisms. Despite this, behavioral studies show that interruption of the actions of any single mediator can relieve signs of pain in experimental animals. We draw attention this paradox. It is difficult to explain how inactivation of one mediator can relieve pain when so many parallel pathways are available.
Highlights
This review outlines aspects of the etiology of neuropathic pain at both the spinal and peripheral level
Released from primary afferents to affect spinal microglia†. *This paper provides indirect evidence, colony stimulating factor 1 (CSF-1) releases BDNF from microglia as monitored by increased dorsal horn excitability, some of the effect of cerebrospinal fluid (CSF)-1 on excitability is abrogated by BDNF binding protein. †Wnt3a may be released from primary afferent terminals after nerve injury but is thought to signal directly to dorsal horn neurons without the intervention of microglia [134]
CCL21 is upregulated in dorsal root ganglion (DRG) following nerve injury, vesicles containing CCL21 are preferentially transported into axons [145], CCL21 affects microglial function [148] and it can be released from terminals of injured or “endangered” neurons [149, 331]. These findings suggest that CCL21 is more likely than MCP1/CCL2 to function as a secondary mediator between primary afferents and microglia following injury [146, 221]
Summary
This review outlines aspects of the etiology of neuropathic pain at both the spinal and peripheral level. Primary mediators sensitize sensory nerve endings, attract additional macrophages and lymphocytes, alter gene expression, promote post-translational modification of proteins, and alter ion channel function in primary afferent neurons This leads to increased excitability, spontaneous activity and the generation of secondary mediators (see Table 2 and Figure 1). Secondary mediators such as colony stimulating factor 1 (CSF-1), chemokine (C-C motif) ligand 21 (CCL21), and wingless-type mammary tumor virus integration site family, member 5A (Wnt5a) are released from primary afferent terminals in the spinal dorsal horn. They affect the properties of spinal microglial cells causing them to release tertiary mediators. The present review will focus on microglia activity within the spinal dorsal horn
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