Chemokines and the pathophysiology of neuropathic pain

Abstract

Chemokines and chemokine receptors are widely expressed by cells of the immune and nervous systems. This review focuses on our current knowledge concerning the role of chemokines in the pathophysiology of chronic pain syndromes. Injury- or disease-induced changes in the expression of diverse chemokines and their receptors have been demonstrated in the neural and nonneural elements of pain pathways. Under these circumstances, chemokines have been shown to modulate the electrical activity of neurons by multiple regulatory pathways including increases in neurotransmitter release through Ca-dependent mechanisms and transactivation of transient receptor channels. Either of these mechanisms alone, or in combination, may contribute to sustained excitability of primary afferent and secondary neurons within spinal pain pathways. Another manner in which chemokines may influence sustained neuronal excitability may be their ability to function as excitatory neurotransmitters within the peripheral and central nervous system. As is the case for traditional neurotransmitters, injury-induced up-regulated chemokines are found within synaptic vesicles. Chemokines released after depolarization of the cell membrane can then act on other chemokine receptor-bearing neurons, glia, or immune cells. Because up-regulation of chemokines and their receptors may be one of the mechanisms that directly or indirectly contribute to the development and maintenance of chronic pain, these molecules may then represent novel targets for therapeutic intervention in chronic pain states.

Fig. 1.

The neural pathway of nociception from primary afferent neurons (PANs) to the superficial lamina in the dorsal horn of the spinal cord. Second-order neurons in the dorsal horn convey the noxious signal to the brainstem, midbrain, and thalamus. Finally, third-order neurons relay the electrical signal to the somatosensory/cingulate cortex and limbic system. Descending modulatory influences arrive in the spinal cord dorsal horn (dashed lines) and are derived from the midbrain periaqueductal gray (PAG), the locus ceruleus, and the rostral ventromedial medulla (RVM).

Fig. 2.

Peripheral and central targets of primary afferent neurons. (Upper) The somas of nociceptive neurons are housed together with myelinating Schwann cells and nonmyelinating Schwann cells (satellite cells) in the dorsal root ganglia (DRG). These pseudounipolar neurons communicate with both peripheral target tissue (epithelia, muscle, and visceral organs) and neuronal/nonneuronal elements of the spinal cord dorsal horn (neurons, microglia, and astrocytes). Some chemokine/receptors are present in both CNS and PNS cellular elements. (Lower) Following injury, compromised sensory neurons and adjacent nonneuronal cells produce chemokines and their receptors within the DRG (n/c indicates no change in mRNA or protein expression). These chemokines can be released within the DRG as well as from axons in peripheral target tissue and spinal cord dorsal horn. Increased cellular signaling between chemokines and receptors may be responsible for changes in neuronal excitability.

Fig. 3.

Crosstalk among chemokine receptors, bradykinin, and transient receptor potential channels (TRP). (Upper) In sensory neurons, treatment with the proinflammatory bradykinin peptide results in hyperalgesia. Bradykinin also enhances the sensitivity of TRPV1 and TRPA1, through a signal transduction cascade involving Gi protein, PLCβ, and PKC. PLCβ hydrolyzes phosphoinositol 4,5-biphosphate (PIP2), an endogenous inhibitor of TRPV1, thereby sensitizing the TRPV1 pain receptor. Activation of PKC can simultaneously produce activation of TRPA1 receptors. (Lower) Nerve injury up-regulates the chemokine receptor, CCR2. Activation of CCR2 by MCP-1 can now sensitize nociceptors via transactivation of the transient receptor potential channels, TRPV1 and TRPA1. Injury-induced up-regulation of MCP-1/CCR2 signaling by sensory neurons may participate sustained excitability of primary afferent neurons.

Fig. 4.

Primary afferent neurons express MCP-1 and CCR2 in association with peripheral neuropathy. Sciatic nerve demyelination injury was induced by lysophosphatidylcholine (LPC) in CCR2-EGFP BAC transgenic mice. DRG were isolated at postoperation day (POD) 14, cryosectioned, and subjected to immunohistochemistry by using a polyclonal anti-MCP-1 antibody. (A–C) Sham-operated control. (D–F) LPC-treated group. Note that many neuronal cell bodies express both MCP-1 and CCR2. In addition, MCP-1 is also observed in numerous axon processes throughout the ganglion. (G–I) TRPV1-expressing nociceptors (red arrows) up-regulated CCR2 expression (yellow arrow). Some of larger neurons that do not express TRPV1 also expressed CCR2 (green arrow). (Scale bars, 100 μm.) [Reproduced with permission from ref. . (Copyright 2007, Blackwell).]