Neuronal hyperexcitability in both injured and adjacent uninjured neurons is associated with states of chronic injury and pain and is likely subject to neuroinflammatory processes. Chronic inflammatory responses are largely orchestrated by chemokines. One chemokine, monocyte chemoattractant protein-1 (MCP-1), in the presence of its cognate receptor, the  chemokine receptor 2 (CCR2), produces neural activity in dissociated neuronal cultures of neonatal dorsal root ganglion (DRG) neurons. Using a neuropathic pain model, chronic compression of the DRG (CCD), we compared anatomically separate populations of noncompressed lumbar DRG (L3͞L6) with compressed lumbar DRG (L4͞L5) for changes in the gene expression of CCR2. In situ hybridization revealed that CCR2 mRNA was up-regulated in neurons and nonneuronal cells present in both compressed L4͞L5 and ipsilateral noncompressed L3͞L6 DRGs at postoperative day 5 (POD5). The total percentages of compressed and noncompressed neurons exhibiting CCR2 mRNA transcripts in L3, L5, and L6 DRG were 33 ؎ 3.5%, 49 ؎ 6.2%, and 41 ؎ 5.6%, respectively, and included cell bodies of small, medium, and large size. In addition, the preferred CCR2 ligand, MCP-1, was up-regulated by POD5 in both compressed L4͞L5 and noncompressed L3͞L6 DRG neurons. Application of MCP-1 to the cell bodies of the intact formerly compressed DRG in vitro produced potent excitatory effects not observed in control ganglia. MCP-1͞CCR2 signaling is directly involved with a chronic compression injury and may contribute to associated neuronal hyperexcitability and neuropathic pain.hyperalgesia ͉ nerve injury ͉ neuropathic pain ͉ peripheral sensitization I nf lammation accompanying peripheral nerve injury frequently produces neuropathic pain symptoms, such as hyperalgesia and allodynia. This hyperalgesia may reflect ongoing or ectopic changes in the excitability of neurons in both injured and adjacent uninjured dorsal root ganglion (DRG) (1). Mechanisms that may contribute to the changes in neuronal activity include altered expression of ion channels, kinases, enzymes, neuropeptides, transcription factors, neurotrophins, and͞or the de novo presence of proinflammatory mediators such as cytokines, chemokines, and their respective receptors. However, current knowledge of the modification of molecular properties in both injured and noninjured adjacent ganglia is limited.Recent studies implicate the  chemokine receptor 2 (CCR2) in the development and maintenance of pain (2-4). CCR2 is a G protein-coupled receptor that is related in structure to other CCRs (5, 6) and is largely thought to be a major regulator of induced macrophage migration (7-9). CCR2 is also constitutively expressed by different types of cells in the central nervous system, including neurons (10, 11), activated astrocytes (12, 13), microglia (3), and neural progenitor cells (14,15).Most CCRs, including CCR2, bind multiple chemokines (16, 17). CCR2 binds a family of closely related -chemokines (C-C) called monocyte chemoattractant proteins (MCP), of whic...
Chronic pain hypersensitivity depends on N-type voltage-gated calcium channels (CaV2.2). However, the use of CaV2.2 blockers in pain therapeutics is limited by side effects that result from inhibited physiological functions of these channels. Here we report suppression of both inflammatory and neuropathic hypersensitivity by inhibiting the binding of the axonal collapsin response mediator protein 2 (CRMP-2) to CaV2.2, thus reducing channel function. A 15-amino acid peptide of CRMP-2 fused to the transduction domain of HIV TAT protein (TAT-CBD3) decreases neurotransmitter release from nociceptive dorsal root ganglion neurons, reduces meningeal blood flow, reduces nocifensive behavior induced by subcutaneous formalin injection or following corneal capsaicin application, and reverses neuropathic hypersensitivity produced by the antiretroviral drug 2’,3’-dideoxycytidine. TAT-CBD3 was mildly anxiolytic but innocuous on sensorimotor and cognitive functions and despair. By preventing CRMP-2-mediated enhancement of CaV2.2 function, TAT-CBD3 alleviates inflammatory and neuropathic hypersensitivity, an approach that may prove useful in managing clinical pain.
BackgroundAnimal and clinical studies have revealed that focal peripheral nerve axon demyelination is accompanied by nociceptive pain behavior. C-C and C-X-C chemokines and their receptors have been strongly implicated in demyelinating polyneuropathies and persistent pain syndromes. Herein, we studied the degree to which chronic nociceptive pain behavior is correlated with the neuronal expression of chemokines and their receptors following unilateral lysophosphatidylcholine (LPC)-induced focal demyelination of the sciatic nerve in rats.ResultsFocal nerve demyelination increased behavioral reflex responsiveness to mechanical stimuli between postoperative day (POD) 3 and POD28 in both the hindpaw ipsilateral and contralateral to the nerve injury. This behavior was accompanied by a bilateral increase in the numbers of primary sensory neurons expressing the chemokine receptors CCR2, CCR5, and CXCR4 by POD14, with no change in the pattern of CXCR3 expression. Significant increases in the numbers of neurons expressing the chemokines monocyte chemoattractant protein-1 (MCP-1/CCL2), Regulated on Activation, Normal T Expressed and Secreted (RANTES/CCL5) and interferon γ-inducing protein-10 (IP-10/CXCL10) were also evident following nerve injury, although neuronal expression pattern of stromal cell derived factor-1α (SDF1/CXCL12) did not change. Functional studies demonstrated that acutely dissociated sensory neurons derived from LPC-injured animals responded with increased [Ca2+]i following exposure to MCP-1, IP-10, SDF1 and RANTES on POD 14 and 28, but these responses were largely absent by POD35. On days 14 and 28, rats received either saline or a CCR2 receptor antagonist isomer (CCR2 RA-[R]) or its inactive enantiomer (CCR2 RA-[S]) by intraperitoneal (i.p.) injection. CCR2 RA-[R] treatment of nerve-injured rats produced stereospecific bilateral reversal of tactile hyperalgesia.ConclusionThese results suggest that the presence of chemokine signaling by both injured and adjacent, uninjured sensory neurons is correlated with the maintenance phase of a persistent pain state, suggesting that chemokine receptor antagonists may be an important therapeutic intervention for chronic pain.
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