title: Glycogen synthase kinase 3 beta regulates glial glutamate transporter protein expression in the spinal dorsal horn in rats with neuropathic pain.
abstract: Dysfunctional glial glutamate transporters and over production of pro-inflammatory cytokines (including interleukin-1β, IL-1β) are two prominent mechanisms by which glial cells enhance neuronal activities in the spinal dorsal horn in neuropathic pain conditions. Endogenous molecules regulating production of IL-1β and glial glutamate functions remain poorly understood. In this study, we revealed a dynamic alteration of GSK3β activities and its role in regulating glial glutamate transporter 1 (GLT-1) protein expression in the spinal dorsal horn and nociceptive behaviors following the nerve injury. Specifically, GSK3β was expressed in both neurons and astrocytes in the spinal dorsal horn. GSK3β activities were suppressed on day 3 but increased on day 10 following the nerve injury. In parallel, protein expression of GLT-1 in the spinal dorsal horn was enhanced on day 3 but reduced on day 10. In contrast to these time-dependent changes, the activation of astrocytes and over-production of IL-1β were found on both day 3 and day 10. Meanwhile, thermal hyperalgesia was observed from day 2 through day 10 and mechanical allodynia from day 4 through day 10. Pre-emptive pharmacological inhibition of GSK3β activities significantly ameliorated thermal hyperalgesia and mechanical allodynia at the late stage but did not have effects at the early stage. These were accompanied with the suppression of GSK3β activities, prevention of decreased GLT-1 protein expression, inhibition of astrocytic activation, and reduction of IL-1β in the spinal dorsal horn on day 10. These data indicate that the increased GSK3β activity in the spinal dorsal horn is attributable to the downregulation of GLT-1 protein expression in neuropathic rats at the late stage. Further, we also demonstrated that the nerve-injury-induced thermal hyperalgesia on day 10 was transiently suppressed by pharmacological inhibition of GSK3β. Our study suggests that GSK3β may be a potential target for the development of analgesics for chronic neuropathic pain.
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, The University of Georgia College of Pharmacy, Athens, GA 30602, USA. Electronic address: hrweng@uga.edu.
authors.forename: Han-Rong
authors.initials: HR
authors.lastname: Weng
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, The University of Georgia College of Pharmacy, Athens, GA 30602, USA.
authors.forename: Mei
authors.initials: M
authors.lastname: Gao
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, The University of Georgia College of Pharmacy, Athens, GA 30602, USA.
authors.forename: Dylan W
authors.initials: DW
authors.lastname: Maixner
mesh_terms: D027322:Amino Acid Transport System X-AG / Q000378:metabolism*; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D004333:Drug Administration Routes; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D027342:Excitatory Amino Acid Transporter 2 / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006930:Hyperalgesia / Q000188:drug therapy / Q000209:etiology; D053583:Interleukin-1beta / Q000378:metabolism; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D051058:Oncogene Protein v-akt / Q000378:metabolism; D010147:Pain Measurement / Q000187:drug effects; D017288:Pain Threshold / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012585:Sciatica / Q000473:pathology*; D012694:Serine / Q000378:metabolism; D013116:Spinal Cord / Q000378:metabolism*; D013844:Thiazoles / Q000627:therapeutic use; D013997:Time Factors; D014508:Urea / Q000031:analogs & derivatives / Q000627:therapeutic use
chemical_list: D027322:Amino Acid Transport System X-AG; D004791:Enzyme Inhibitors; D027342:Excitatory Amino Acid Transporter 2; D005904:Glial Fibrillary Acidic Protein; D053583:Interleukin-1beta; C493395:Slc1a2 protein, rat; D013844:Thiazoles; D012694:Serine; C479831:N-(4-methoxybenzyl)-N'-(5-nitro-1,3-thiazol-2-yl)urea; D014508:Urea; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D051058:Oncogene Protein v-akt; D038362:Glycogen Synthase Kinase 3
keywords: Dorsal horn; GSK3beta; GSK3β; Glutamate transporter; IL-1β; Interleukin-1beta; Nociception; Pain