CCL-1 in the spinal cord contributes to neuropathic pain induced by nerve injury

Neuropathic pain (also classified as chronic or malignant pain) is associated with nerve injury of multiple aetiology that includes acute trauma, diabetes, cancer, infection and autoimmune pathology.1 Pathogenesis of neuropathic pain reflects complex remodelling of the spinal cord, with primary role attributed to change of synaptic transmission and activation of neuroglial cells, astrocytes and microglia.2, 3, 4 Glutamate, the major excitatory neurotransmitter in the brain and spinal cord, exerts its postsynaptic effects via a diverse set of ionotropic and metabotropic membrane receptors. The glutamate ionotropic N-methyl-𝒟-aspartate receptors (NMDARs), specifically those localized in the dorsal horn of the spinal cord, are critically involved in nociceptive transmission and synaptic plasticity and have long been considered a target for the treatment of neuropathic pain.5, 6 The native neuronal NMDAR is a tetramer that consists of two NR1 and two NR2 subunits.7 Phosphorylation of multiple sites in the cytoplasmic C termini of the NR1 and NR2 subunits is known to modulate NMDAR activity and affect synaptic transmission.8, 9, 10 There are many reports that nerve injury triggers reactive changes in peripheral immune system and in neuroglial cells in both peripheral and central nervous systems.4, 11, 12 In the periphery, activation of Schwann cells and resident macrophages recruit hematogenous immune cells, which subsequently invade the injured nerves.12, 13, 14 In the spinal dorsal horn receiving the injured sensory afferents, activation of microglia is commonly associated with early establishment stages of neuropathic pain.2, 15, 16 Cytokines such as interleukin-1β (IL-1β), tumour necrosis factor-α (TNF-α) and IL-6, which originate from the peripheral injured area or from activated neuroglial cells in the spinal cord, are known to alter synaptic transmission in the dorsal horn.13, 14 Chemokines and their receptors are widely expressed in immune cells and in the nervous system.17, 18 Recent studies have shown that chemokines C-C motif ligand 2 (CCL-2) and CX3CL-1 induce tactile allodynia (when non-painful innoxious stimuli become painful) through activation of spinal cord microglia.17, 19 These reactive changes mediated through cytokines and chemokines develop in parallel with tactile allodynia, the latter being the main symptom of neuropathic pain.20 CCL-1 (also known as thymus-derived chemotactic agent 3) is one of the well-characterized chemokines and is classified into the same CC chemokine group as CCL-2. CCL-1 is secreted by activated T cell, mast cells and endothelial cells and has important role as the chemoattractant for neutrophils and monocytes.21 Although effects of CCL-1 on the immune cells are well characterized, the roles of CCL-1 in the central nervous system, and especially in the development of neuropathic pain, remain unclear. In this report, we found that CCL-1 is involved in the development of tactile allodynia following peripheral nerve injury through enhancement of spinal nociceptive transmission and activation of glial cells with subsequent release of cytokines.