Chemokines: integrators of pain and inflammation

Abstract

Chronic (neuropathic) pain is one of the most widespread and intractable of human complaints, as well as being one of the most difficult syndromes to treat successfully with drugs or surgery. The development of new therapeutic approaches to the treatment of painful neuropathies requires a better understanding of the mechanisms that underlie the development of these chronic pain syndromes. It is clear that inflammatory responses often accompany the development of neuropathic pain, and here we discuss the idea that chemokines might be key to integrating the development of pain and inflammation and could furnish new leads in the search for effective analgesic agents for the treatment of painful neuropathies.

Figure 1. Schematic diagram of peripheral nervous sytem

The soma of the general somatic primary afferent neurons are housed in the dorsal root ganglia (DRG). These pseudo-unipolar neurons with a peripheral process that contacts with target tissues and a central process in the spinal cord dorsal horn are closely associated with numerous non-neuronal cells that are present in all three locations. Central terminations of DRG cells in the spinal cord are surrounded by central nervous system neurons, oligodendrocytes, astrocytes and microglia. Cells associated with the normal DRG include myelinating Schwann cells and non-myelinating Schwann cells (satellite cells), endothelial cells, fibroblasts, mast cells, resident endoneurial macrophages and occasional lymphoctyes. The environment of the peripheral nerve is similar to the DRG milieu, with the exception of satellite cells. These are absent in the peripheral nerve; however, non-myelinating Schwann cells are present in the form of Remak Schwann cells that surround and support nerve fibres (Remak bundles). On injury or infection, compromised neurons and/or adjacent cells produce molecules that can then be responsible for changes in sensitivity.

Figure 2. Chemokine receptors expressed by cultured rat neonatal dorsal rat ganglia (DRG) neurons

A | Trace shows an increase in Ca²⁺ in a cultured neonatal DRG neuron in response to the chemokine monocyte chemoattractant protein-1 (MCP1)/CCL2 or to bradykinin (BK). Note that in this particular cell the chemokines macrophage inflammatory protein-1β (MIP1β) and Eotaxin (E) were both ineffective. B | Staining of rat neonatal DRG neurons for CXCR4 receptor expression. The overlay illustrates co-localization of CXCR4 with substance P in cultured DRG neurons. C | Electro physiological effects of chemokines on cultured rat DRG neurons. a–c | Current clamp recordings show that addition of macrophage-derived chemokine (MDC) (b) lowers the action potential threshold. This effect disappears following washout of the chemokine (c). The irritant pain-producing substance capsaicin (d) prolongs the action potential to the same neuron and reversal of its effect (e). Addition of the HIV-1 coat protein gp120 (f) also reversibly lowers the threshold for action potential induction in cultured neonatal DRG neurons. D | Data illustrate the threshold for paw removal from a mechanical stimulus at several time points after injection of rats with saline, bradykinin, RANTES (regulated on activation, normal T cell expressed and secreted), stromal-cell-derived factor-1α (SDF1α), MDC, gp120 SIV and gp120 HIV-1. Graphs show that the injection of chemokines, bradykinin or gp120 into the rat paw produces allodynia. Panels A–D modified, with permission, from REF. © 2001 Society for Neuroscience. BL, baseline; pA, picoampere.

Figure 3. CCR2 mRNA expression in compressed and adjacent, non-compressed dorsal root ganglia (DRG)

a | CCR2 sense riboprobe hybridization in representative compressed L5 DRG at post-operative day (POD) 5. b | Sham-treated L5 DRG expression levels of chemokine (CC motif) receptor CCR2 mRNA at POD5. c,d | Compressed L5 DRG (c) and adjacent non-compressed L6 DRG (d) do not show CCR2 mRNA expression at POD1. e,f | Compressed L5 DRG (e) and adjacent, non-compressed L6 (f) show only neuronal CCR2 mRNA expression (indicated by arrows) at POD3. g,h | Compressed L5 DRG (g) at POD 5 also show high levels of CCR2 mRNA expression predominantly in non-neuronal cells such as satellite cells, but many more neurons are positive for CCR2 mRNA transcripts (indicated by arrows). High levels of CCR2 mRNA are present in predominantly non-neuronal cells and some neurons (indicated by arrows) of adjacent, non-compressed L6 (h) DRG at POD5. In panels g and h, asterisks indicate non-labelled neurons. Reproduced, with permission, from REF. © (2005) National Academy of Science.

Figure 4. Possible chemokine receptor function in the context of HIV-1 neuropathy

The viral coat protein gp120 can bind to the chemokine (CC motif) receptors CCR5 and CXCR4 and can also act as an agonist or antagonist of chemokine action, depending on the circumstances. For example, gp120 can directly excite cultured dorsal root ganglia (DRG) neurons in a similar mode to chemokines and direct injection of gp120 into the rat paw produces allodynia (FIG. 2). In addition, prolonged treatment of DRG neurons with gp120 produces apoptosis. Therefore, gp120 might induce some features of HIV-1 neuropathy through direct effects on chemokine receptors that are expressed by DRG neurons. It has also been suggested that gp120 could produce effects through the activation of CXCR4 receptors expressed by Schwann cells,. According to one hypothesis, activation of these receptors by gp120 causes Schwann cells to secrete the chemokine RANTES (regulated on activation, normal T cell expressed and secreted). RANTES can then activate CCR5 receptors expressed by DRG neurons, which could produce pain through direct excitation. RANTES can also stimulate tumour-necrosis factor-α (TNFα) production by DRG neurons. TNFα might then act in a cell-autonomous manner to produce excitation and pain or neuronal apoptosis. Interestingly, TNFα also suppresses the expression of CXCR4 receptors by Schwann cells and is toxic to these cells. So, it seems that HIV-1 could trigger painful neuropathies in several ways, ranging from the overall consequences of neuroinflammation to the viral-induced activation of chemokine-receptor-induced events in neurons and glia. TNFR, tumour-necrosis factor receptor.

Figure 5. Possible chemokine-mediated signal transduction in dorsal root ganglia neurons in association with neuropathic pain

Neurons can synthesize the chemokine monocyte chemoattractant protein-1 (MCP1), and also respond to this chemokine via expression of its chemokine (CC motif) receptor CCR2 (REF. 50). Activation of CCR2 could effect transactivation of the transient receptor potential vanilloid receptor-1 (TRPV1) channel, as has recently been shown for the structurally related CCR1 chemokine receptor, resulting in depolarization and action potential generation. MCP1 can also attract leukocytes into the ganglia. Some of these can secrete endorphins– that activate opiate receptors and reduce neuronal excitability. In addition, activation of CCR2 receptors by MCP1 can cross-desensitize opiate receptor function–.