title: Dorsal root ganglion neurons become hyperexcitable and increase expression of voltage-gated T-type calcium channels (Cav3.2) in paclitaxel-induced peripheral neuropathy.
abstract: Here, it is shown that paclitaxel-induced neuropathy is associated with the development of spontaneous activity (SA) and hyperexcitability in dorsal root ganglion (DRG) neurons that is paralleled by increased expression of low-voltage-activated calcium channels (T-type; Cav3.2). The percentage of DRG neurons showing SA and the overall mean rate of SA were significantly higher at day 7 in rats receiving paclitaxel treatment than in rats receiving vehicle. Cav3.2 expression was increased in L4-L6 DRG and spinal cord segments in paclitaxel-treated rats, localized to small calcitonin gene-related peptide and isolectin B4 expressing DRG neurons and to glial fibrillary acidic protein-positive spinal cord cells. Cav3.2 expression was also co-localized with toll-like receptor 4 (TLR4) in both the DRG and the dorsal horn. T-type current amplitudes and density were increased at day 7 after paclitaxel treatment. Perfusion of the TLR4 agonist lipopolysaccharide directly activated DRG neurons, whereas this was prevented by pretreatment with the specific T-type calcium channel inhibitor ML218 hydrochloride. Paclitaxel-induced behavioral hypersensitivity to mechanical stimuli in rats was prevented but not reversed by spinal administration of ML218 hydrochloride or intravenous injection of the TLR4 antagonist TAK242. Paclitaxel induced inward current and action potential discharges in cultured human DRG neurons, and this was blocked by ML218 hydrochloride pretreatment. Furthermore, ML218 hydrochloride decreased firing frequency in human DRG, where spontaneous action potentials were present. In summary, Cav3.2 in concert with TLR4 in DRG neurons appears to contribute to paclitaxel-induced neuropathy.
authors.affiliation: Departments of Anesthesia and Pain Medicine and.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Claudio Esteves
authors.initials: CE
authors.lastname: Tatsui
authors.affiliation: Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Laurence D
authors.initials: LD
authors.lastname: Rhines
authors.affiliation: Department of Neurosurgery, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Robert Y
authors.initials: RY
authors.lastname: North
authors.affiliation: Duke University School of Medicine, Durham, NC, USA.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Harrison
authors.affiliation: The University of Texas Health Science Center, Houston, TX, USA.
authors.forename: Ryan M
authors.initials: RM
authors.lastname: Cassidy
authors.affiliation: The University of Texas Health Science Center, Houston, TX, USA.
authors.forename: Caj A
authors.initials: CA
authors.lastname: Johansson
authors.affiliation: The University of Texas Health Science Center, San Antonio, TX, USA.
authors.forename: Alyssa K
authors.initials: AK
authors.lastname: Kosturakis
authors.affiliation: Philadelphia College of Osteopathic Medicine, Suwanee, GA, USA.
authors.forename: Denaya D
authors.initials: DD
authors.lastname: Edwards
authors.affiliation: Departments of Anesthesia and Pain Medicine and.
authors.forename: Hongmei
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Departments of Anesthesia and Pain Medicine and.
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Dougherty
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects / Q000494:pharmacology; D053961:Azabicyclo Compounds / Q000627:therapeutic use; D001549:Benzamides / Q000627:therapeutic use; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000627:therapeutic use; D020747:Calcium Channels, T-Type / Q000378:metabolism*; D004195:Disease Models, Animal; D005727:Ganglia, Spinal / Q000473:pathology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D006930:Hyperalgesia / Q000209:etiology*; D008297:Male; D017239:Paclitaxel / Q000009:adverse effects / Q000494:pharmacology; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced / Q000150:complications* / Q000473:pathology* / Q000517:prevention & control; D051381:Rats; D017207:Rats, Sprague-Dawley; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000378:metabolism*; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism; D013449:Sulfonamides / Q000627:therapeutic use; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D053961:Azabicyclo Compounds; D001549:Benzamides; C509958:Cacna1h protein, rat; D002121:Calcium Channel Blockers; D020747:Calcium Channels, T-Type; C000611565:ML218 compound; D013449:Sulfonamides; C495347:Tlr4 protein, rat; D051197:Toll-Like Receptor 4; C507035:ethyl 6-(N-(2-chloro-4-fluorophenyl)sulfamoyl)cyclohex-1-ene-1-carboxylate; D015740:Calcitonin Gene-Related Peptide; D017239:Paclitaxel