title: Spinal astrocyte gap junction and glutamate transporter expression contributes to a rat model of bortezomib-induced peripheral neuropathy.
abstract: There is increasing evidence implicating astrocytes in multiple forms of chronic pain, as well as in the specific context of chemotherapy-induced peripheral neuropathy (CIPN). However, it is still unclear what the exact role of astrocytes may be in the context of CIPN. Findings in oxaliplatin and paclitaxel models have displayed altered expression of astrocytic gap junctions and glutamate transporters as means by which astrocytes may contribute to observed behavioral changes. The current study investigated whether these changes were also generalizable to the bortezomib CIPN. Changes in mechanical sensitivity were verified in bortezomib-treated animals, and these changes were prevented by co-treatment with a glial activation inhibitor (minocycline), a gap junction decoupler (carbenoxolone), and by a glutamate transporter upregulator (ceftriaxone). Immunohistochemistry data at day 30 in bortezomib-treated animals showed increases in expression of glial fibrillary acidic protein (GFAP) and connexin 43 but a decrease in GLAST expression. These changes were prevented by co-treatment with minocycline. Follow-up Western blotting data showed a shift in connexin 43 from a non-phosphorylated state to a phosphorylated state, indicating increased trafficking of expressed connexin 43 to the cell membrane. These data suggest that increases in behavioral sensitivity to cutaneous stimuli may be tied to persistent synaptic glutamate resulting from increased calcium flow between spinal astrocytes.
authors.affiliation: The Department of Anesthesiology and Pain Medicine Research, The University of Texas M.D. Anderson Cancer Center, 1400 Holcombe, Unit 409, Houston, TX 77030, Unites States.
authors.forename: C R
authors.initials: CR
authors.lastname: Robinson
authors.affiliation: The Department of Anesthesiology and Pain Medicine Research, The University of Texas M.D. Anderson Cancer Center, 1400 Holcombe, Unit 409, Houston, TX 77030, Unites States. Electronic address: pdougherty@mdanderson.org.
authors.forename: P M
authors.initials: PM
authors.lastname: Dougherty
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D000069286:Bortezomib / Q000633:toxicity*; D002229:Carbenoxolone / Q000494:pharmacology; D002443:Ceftriaxone / Q000494:pharmacology; D002491:Central Nervous System Agents / Q000494:pharmacology; D018031:Connexin 43 / Q000378:metabolism; D004195:Disease Models, Animal; D027341:Excitatory Amino Acid Transporter 1 / Q000378:metabolism*; D027342:Excitatory Amino Acid Transporter 2 / Q000378:metabolism*; D017629:Gap Junctions / Q000378:metabolism; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006930:Hyperalgesia / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D008297:Male; D008911:Minocycline / Q000494:pharmacology; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology
chemical_list: D002491:Central Nervous System Agents; D018031:Connexin 43; D027341:Excitatory Amino Acid Transporter 1; D027342:Excitatory Amino Acid Transporter 2; C580592:Gja1 protein, rat; D005904:Glial Fibrillary Acidic Protein; C493395:Slc1a2 protein, rat; C493392:Slc1a3 protein, rat; D000069286:Bortezomib; D002443:Ceftriaxone; D008911:Minocycline; D002229:Carbenoxolone
keywords: GFAP; GLAST; GLT-1; bortezomib; connexin 43; minocycline