Peripheral nerve injury produces molecular and cellular changes that result in multiple forms of neuronal plasticity and anatomical reorganization at various levels of the peripheral and central nervous systems. Oligo-dendrocytes, astrocytes, and microglia form a large group of CNS glial cells. Although often underappreciated, a substantial body of evidence has accumulated showing that peripheral nerve injury leads to activation of glia in the spinal cord implicating astrocytes and particularly microglia.89,123
Microglia are immune-derived cells and represent 5-10 percent of glia in the CNS.154 Microglia are said to be resting under normal conditions and do not actively influence nociceptive processing. However, microglia become activated by events such as CNS injury, microbial invasion, and in some pain states. Following peripheral nerve lesions, spinal microglia appear to migrate to the relevant spinal segments, thus increasing the local micro-glial population, and become activated involving a stereotypic series of changes including morphological alteration (they become hypertrophic and ameobiod), gene expression, and function. Moreover, activated microglia produce and release various chemical mediators, including proinflammatory cytokines, chemokines, and other potentially pain-producing substances, that can produce immunological actions and can also act on neurons to alter their function (Figure 1.6).89155 The status of microglia in the spinal cord has been examined in a variety of nerve injury models and substantial evidence, both direct and indirect, indicates that microgliosis fundamentally contributes to the pathophysiology of neuropathic pain.20,22, 156,157,158 This is supported by several studies that have shown specific microglial inhibitors and/or modulators, such as fluorocitrate and minocycline block, and/or reverse neuropathic states.21,22,159,160
Figure 1.7 The effect of morphine in nerve-injured mice. Dose-response curves of morphine in sham-operated (sham) and nerve-injured (injured) mice after subcutaneous (s.c.), intrathecal (i.t.), and intracerebroventricular (i.c.v.) injection with the Hargreaves thermal paw withdrawal test. Graphs show dose-response curves of (a) s.c., (b) i.t., and (c) i.c.v. morphine in sham-operated and nerve-injured mice at seven days following nerve ligation. The data are presented as AUC analgesia. Each data point represents the mean s.e.m. from six mice. Redrawn from Rashid et al., 2000142 with permission from The American Society for Pharmacology and Experimental Therapeutics.
It is not clear what factors activate spinal microglia in peripheral neuropathic pain states. Several molecules have been implicated, including macrophage colony-stimulating factor (MCSF),161 IL-6,162 substance P, ATP, and the chemokines, fracktalkine,163 and CCL2.164 Activated microglia express various molecules allowing them to respond to such stimuli, including the ATP gated ligand-gated cation channels, P2 x 4,165 and P2 x 7,166 and the chemotactic cytokine receptor 2 (CCR2), a receptor for CCL2/MCP-1. Recent evidence suggests that ATP-stimu-lated microglia signal to lamina I neurons via their release of BDNF, causing a depolarizing shift in the neuronal anion reversal potential inverting the polarity of currents activated by GABA. This means that GABA now results in excitation of the cell as opposed to inhibition.158 Evidence for a role of CCR2 in nerve injury-induced hypersensi-tivity95 comes from mutant mice lacking the receptor.
However, as CCR2 is also up-regulated in the peripheral nerve, at the site of the nerve injury and in the DRG, it is unclear whether spinal microglia expressed CCR2 is responsible. The cannabinoid receptor subtype CB2 may also be expressed by spinal microglia after nerve injury and therefore cannabinoids may play a role as modulators of neuropathic pain via actions on microglia.167 Accordingly, systemically administered CB2 agonists can inhibit nerve injury-evoked pain behaviors.95,168 However, CB2 agonists might act in the periphery and therefore the role of microglial CB2 receptors is, at present, unclear.169,170 The recruitment of microglia is commonly associated with the activation (phosphorylation) of p38 MAP (MAP) kinase and MAP kinase ERK (extracellular signalregulated kinase) in the spinal cord. Phosphorylation of p38 is probably a key intracellular signal in the microglial response in neuropathic pain157,171 and the sequential activation of ERK in neurons, then microglia, and finally astrocytes in a neuropathic pain model172 suggests that microgial activation might be the first step in a cascade of immune responses in the CNS.86, 94 The aforementioned molecules expressed by activated microglia in neuropathic pain states, or associated intracellular signaling cascades may be potential analgesic targets.
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