Abstract
Chemokines are known to have a role in the nervous system, influencing a range of processes including the development of chronic pain. To date there are very few studies describing the functions of the chemokine lymphotactin (XCL1) or its receptor (XCR1) in the nervous system. We investigated the role of the XCL1-XCR1 axis in nociceptive processing, using a combination of immunohistochemical, pharmacological and electrophysiological techniques. Expression of XCR1 in the rat mental nerve was elevated 3 days following chronic constriction injury (CCI), compared with 11 days post-CCI and sham controls. XCR1 co-existed with neuronal marker PGP9.5, leukocyte common antigen CD45 and Schwann cell marker S-100. In the trigeminal root and white matter of the brainstem, XCR1-positive cells co-expressed the oligodendrocyte marker Olig2. In trigeminal subnucleus caudalis (Vc), XCR1 immunoreactivity was present in the outer laminae and was colocalized with vesicular glutamate transporter 2 (VGlut2), but not calcitonin gene-related peptide (CGRP) or isolectin B4 (IB4). Incubation of brainstem slices with XCL1 induced activation of c-Fos, ERK and p38 in the superficial layers of Vc, and enhanced levels of intrinsic excitability. These effects were blocked by the XCR1 antagonist viral CC chemokine macrophage inhibitory protein-II (vMIP-II). This study has identified for the first time a role for XCL1-XCR1 in nociceptive processing, demonstrating upregulation of XCR1 at nerve injury sites and identifying XCL1 as a modulator of central excitability and signaling via XCR1 in Vc, a key area for modulation of orofacial pain, thus indicating XCR1 as a potential target for novel analgesics.
Highlights
Chemokines are a large family of small, secreted proteins divided into four subgroups – CXC, CC, C and CX3C – according to the number and positioning of the highly conserved cysteine residues in their amino acid sequence (White et al, 2005)
XCR1 is expressed in the peripheral nervous system
Immunohistochemical labeling for XCR1 was present in the rat mental nerve 3 days following constriction injury (CCI) (Fig. 1); no labeling was present in the mental nerves of shamoperated or naıve animals
Summary
Chemokines are a large family of small, secreted proteins divided into four subgroups – CXC, CC, C and CX3C – according to the number and positioning of the highly conserved cysteine residues in their amino acid sequence (White et al, 2005). An increasing number of studies have demonstrated an important role for chemokine signaling in the nervous system (Rostene et al, 2007), where they have diverse effects in a range of physiological and pathological processes, regulating neuronal development, neuroinflammation and synaptic transmission.
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