title: Neuronal CCL21 up-regulates microglia P2X4 expression and initiates neuropathic pain development.
abstract: Up-regulation of P2X4 receptors in spinal cord microglia is crucial for tactile allodynia, an untreatable pathological pain reaction occurring after peripheral nerve injury. How nerve injury in the periphery leads to this microglia reaction in the dorsal horn of the spinal cord is not yet understood. It is shown here that CCL21 was rapidly expressed in injured small-sized primary sensory neurons and transported to their central terminals in the dorsal horn. Intrathecal administration of a CCL21-blocking antibody diminished tactile allodynia development in wild-type animals. Mice deficient for CCL21 did not develop any signs of tactile allodynia and failed to up-regulate microglial P2X4 receptor expression. Microglia P2X4 expression was enhanced by CCL21 application in vitro and in vivo. A single intrathecal injection of CCL21 to nerve-injured CCL21-deficient mice induced long-lasting allodynia that was undistinguishable from the wild-type response. This effect of CCL21 injection was strictly dependent on P2X4 receptor function. Since neuronal CCL21 is the earliest yet identified factor in the cascade leading to tactile allodynia, these findings may lead to a preventive therapy in neuropathic pain.
authors: Department of Psychiatry and Psychotherapy, Section of Molecular Psychiatry, University of Freiburg, Freiburg, Germany.
authors: Knut
authors: K
authors: Biber
authors: Makoto
authors: M
authors: Tsuda
authors: Hidetoshi
authors: H
authors: Tozaki-Saitoh
authors: Keiko
authors: K
authors: Tsukamoto
authors: Emika
authors: E
authors: Toyomitsu
authors: Takahiro
authors: T
authors: Masuda
authors: Hendrikus
authors: H
authors: Boddeke
authors: Kazuhide
authors: K
authors: Inoue
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D054421:Chemokine CCL21 / Q000378:metabolism*; D017931:DNA Primers / Q000235:genetics; D005786:Gene Expression Regulation / Q000502:physiology; D006930:Hyperalgesia / Q000378:metabolism* / Q000473:pathology; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000378:metabolism*; D009437:Neuralgia / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D010147:Pain Measurement; D058848:Receptors, Purinergic P2X4 / Q000378:metabolism*; D013127:Spinal Nerves / Q000293:injuries*; D018709:Statistics, Nonparametric
chemical_list: D054421:Chemokine CCL21; D017931:DNA Primers; D058848:Receptors, Purinergic P2X4