title: Induction of monocyte chemoattractant protein-1 (MCP-1) and its receptor CCR2 in primary sensory neurons contributes to paclitaxel-induced peripheral neuropathy.
abstract: The use of paclitaxel (Taxol), a microtubule stabilizer, for cancer treatment is often limited by its associated peripheral neuropathy (chemotherapy-induced peripheral neuropathy [CIPN]), which predominantly results in sensory dysfunction, including chronic pain. Here we show that paclitaxel CIPN was associated with induction of chemokine monocyte chemoattractant protein-1 (MCP-1) and its cognate receptor CCR2 in primary sensory neurons of dorsal root ganglia. Immunostaining revealed that MCP-1 was mainly expressed in small nociceptive neurons whereas CCR2 was expressed in large and medium-sized myelinated neurons. Direct application of MCP-1 consistently induced intracellular calcium increases in dorsal root ganglia large and medium-sized neurons but not in small neurons mainly dissociated from paclitaxel-treated but not vehicle-treated animals. Paclitaxel also induced increased expression of MCP-1 in spinal astrocytes, but no CCR2 signal was detected in the spinal cord. Local blockade of MCP-1/CCR2 signaling by anti-MCP-1 antibody or CCR2 antisense oligodeoxynucleotides significantly attenuated paclitaxel CIPN phenotypes including mechanical hypersensitivity and loss of intraepidermal nerve fibers in hindpaw glabrous skin. These results suggest that activation of paracrine MCP-1/CCR2 signaling between dorsal root ganglion neurons plays a critical role in the development of paclitaxel CIPN, and targeting MCP-1/CCR2 signaling could be a novel therapeutic approach.
  
  
  CONCLUSIONS
  CIPN is a severe side effect accompanying paclitaxel chemotherapy and lacks effective treatments. The current study suggests that blocking MCP-1/CCR2 signaling could be a new therapeutic strategy to prevent or reverse paclitaxel CIPN. This preclinical evidence encourages future clinical evaluation of this strategy.
authors.affiliation: Department of Anesthesia and Pain Medicine Research, The University of Texas M.D. Anderson Cancer Center, Houston, Texas. Electronic address: haijun.zhang@mdanderson.org.
authors.forename: Haijun
authors.initials: H
authors.lastname: Zhang
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Boyette-Davis
authors.forename: Alyssa K
authors.initials: AK
authors.lastname: Kosturakis
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Seo-Yeon
authors.initials: SY
authors.lastname: Yoon
authors.forename: Edgar T
authors.initials: ET
authors.lastname: Walters
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Dougherty
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects*; D002118:Calcium / Q000378:metabolism; D018932:Chemokine CCL2 / Q000187:drug effects*; D005260:Female; D005727:Ganglia, Spinal / Q000187:drug effects / Q000473:pathology; D007150:Immunohistochemistry; D007278:Injections, Spinal; D017239:Paclitaxel / Q000009:adverse effects*; D017288:Pain Threshold / Q000187:drug effects; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced* / Q000473:pathology; D010812:Physical Stimulation; D020671:Posterior Horn Cells / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D054390:Receptors, CCR2 / Q000187:drug effects*; D011984:Sensory Receptor Cells / Q000187:drug effects*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D054390:Receptors, CCR2; D017239:Paclitaxel; D002118:Calcium
keywords: CCR2; MCP-1; Paclitaxel; dorsal root ganglion; neuropathy