title: The role of inversely operating glutamate transporter in the paradoxical analgesia produced by glutamate transporter inhibitors.
abstract: Controlling extracellular glutamate level in a physiological range is important to maintain normal sensory transmission. Here, we investigated the paradoxical action of glutamate transporters in the rat formalin test to elucidate a possible role of inversely operating transporters in its analgesic mechanism. The effects of glutamate transporter inhibitor on formalin-induced pain behavior were examined. Then we performed a microdialysis study to clarify the differential change in extracellular glutamate concentration by intrathecal administration of transportable and non-transportable blockers. And we further investigated the mechanism pharmacologically via pretreatment with antagonists of various receptors and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL) staining. Intrathecally-injected glutamate transporter inhibitors, non-transportable DL-threo-β-benzyloxyaspartat (TBOA) and transportable trans-pyrrolidine-2,4-dicarboxylic acid (t-PDC), produced paradoxical antinociception in the formalin test. In normal rats, inhibition of the glutamate transporter increased extracellular glutamate. In the formalin model rats, TBOA suppressed while t-PDC enhanced glutamate release. When tPDC was pretreated 30min prior to formalin injection, glutamate release was blocked. Blocking α-2 adrenergic receptors reversed the tPDC analgesia. Increased apoptosis was not apparent in the spinal dorsal horn of tPDC-treated rats compared to the control group. These data suggest that glutamate transporters in a formalin-induced pain state work in a reverse mode and can be blocked from releasing glutamate by TBOA and preloaded tPDC. The analgesic mechanism of TBOA may be related to the blockade of inversely operating transporter, and that of tPDC may be associated with the activation of noradrenergic neurotransmission but not with dorsal horn neurotoxicity.
authors.affiliation: Department of Anesthesiology and Pain Medicine, Chonnam National University Medical School, Gwangju, Republic of Korea; Center for Creative Biomedical Scientists, Chonnam National University Medical School, Gwangju, Republic of Korea; Chonnam National University Hospital Biomedical Research Institute, Gwangju, Republic of Korea. Electronic address: kimwm@jnu.ac.kr.
authors.forename: Woong Mo
authors.initials: WM
authors.lastname: Kim
authors.affiliation: Center for Creative Biomedical Scientists, Chonnam National University Medical School, Gwangju, Republic of Korea.
authors.forename: Joo Wung
authors.initials: JW
authors.lastname: Chae
authors.affiliation: Department of Anesthesiology and Pain Medicine, Chonnam National University Medical School, Gwangju, Republic of Korea.
authors.forename: Bong Ha
authors.initials: BH
authors.lastname: Heo
authors.affiliation: Department of Anesthesiology and Pain Medicine, Chonnam National University Medical School, Gwangju, Republic of Korea.
authors.forename: Keun Suk
authors.initials: KS
authors.lastname: Park
authors.affiliation: Department of Forensic Medicine, Chonnam National University Medical School, Gwangju, Republic of Korea.
authors.forename: Hyung Seok
authors.initials: HS
authors.lastname: Kim
authors.affiliation: Department of Anesthesiology and Pain Medicine, Chonnam National University Medical School, Gwangju, Republic of Korea.
authors.forename: Hyung Gon
authors.initials: HG
authors.lastname: Lee
authors.affiliation: Department of Anesthesiology and Pain Medicine, Chonnam National University Medical School, Gwangju, Republic of Korea.
authors.forename: Jeong Il
authors.initials: JI
authors.lastname: Choi
authors.affiliation: Department of Anesthesiology and Pain Medicine, Chonnam National University Medical School, Gwangju, Republic of Korea.
authors.forename: Myung Ha
authors.initials: MH
authors.lastname: Yoon
mesh_terms: D058669:Adrenergic alpha-2 Receptor Antagonists / Q000494:pharmacology; D027322:Amino Acid Transport System X-AG / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D001224:Aspartic Acid / Q000494:pharmacology*; D003998:Dicarboxylic Acids / Q000494:pharmacology*; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D005557:Formaldehyde / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism; D008297:Male; D059225:Nociception / Q000187:drug effects; D011759:Pyrrolidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D058669:Adrenergic alpha-2 Receptor Antagonists; D027322:Amino Acid Transport System X-AG; D000700:Analgesics; D003998:Dicarboxylic Acids; D011759:Pyrrolidines; C120673:benzyloxyaspartate; D005557:Formaldehyde; D001224:Aspartic Acid; D018698:Glutamic Acid; C083486:pyrrolidine-2,4-dicarboxylic acid
keywords: Glutamate; Glutamate transporter; Inflammatory pain; Microdialysis