title: Blockade of spinal glutamate recycling produces paradoxical antinociception in rats with orofacial inflammatory pain.
abstract: In our current study, we investigated the role of spinal glutamate recycling in the development of orofacial inflammatory pain. DL-threo-β-benzyloxyaspartate (TBOA) or methionine sulfoximine (MSO) was administered intracisternally to block spinal glutamate transporter and glutamine synthetase activity in astroglia. Intracisternal administration of high dose TBOA (10 μg) produced thermal hyperalgesia in naïve rats but significantly attenuated the thermal hyperalgesia in rats that had been pretreated with interleukin (IL)-1β or Complete Freund's Adjuvant (CFA). In contrast, intracisternal injection of MSO produced anti-hyperalgesic effects against thermal stimuli in CFA-treated rats only. To confirm the paradoxical antinociceptive effects of TBOA and MSO, we examined changes in c-Fos expression in the medullary dorsal horn produced by thermal stimulation in naïve, IL-1β-, or CFA-treated rats, after intracisternal injections of TBOA and MSO. Intracisternal administration of TBOA significantly increased c-Fos immunoreactivity in naïve rats. In contrast, intracisternal administration of TBOA significantly decreased the up-regulation of c-Fos immunoreactivity in the medullary dorsal horn of IL-1β- and CFA-treated rats. However, intracisternal injection of MSO blocked the up-regulation of c-Fos immunoreactivity in CFA-treated rats only. We also investigated the effects of botulinum toxin type A (BoNT-A) on TBOA-induced paradoxical antinociception in CFA-treated rats, as BoNT-A inhibits the release of neurotransmitters, including glutamate. BoNT-A treatment reversed behavioral responses produced by intracisternal administration of TBOA in CFA-treated rats. These results suggest that the paradoxical responses produced by blocking glutamate transporters under inflammatory pain conditions are mediated by the modulation of glutamate release from presynaptic terminals. Moreover, blockade of glutamate reuptake could represent a new therapeutic target for the treatment of chronic inflammatory pain conditions.
authors.affiliation: Department of Oral Physiology, School of Dentistry, Kyungpook National University, Daegu, South Korea. Electronic address: kuiye@hanmail.net.
authors.forename: Kui Y
authors.initials: KY
authors.lastname: Yang
authors.affiliation: Department of Oral Physiology, School of Dentistry, Kyungpook National University, Daegu, South Korea. Electronic address: canine77@hanmail.net.
authors.forename: Jun H
authors.initials: JH
authors.lastname: Mun
authors.affiliation: Department of Oral Physiology, School of Dentistry, Kyungpook National University, Daegu, South Korea. Electronic address: turtles1@hanmail.net.
authors.forename: Ki D
authors.initials: KD
authors.lastname: Park
authors.affiliation: Department of Oral Physiology, School of Dentistry, Kyungpook National University, Daegu, South Korea. Electronic address: i-mjh@hanmail.net.
authors.forename: Min J
authors.initials: MJ
authors.lastname: Kim
authors.affiliation: Department of Oral Physiology, School of Dentistry, Kyungpook National University, Daegu, South Korea. Electronic address: jsju@knu.ac.kr.
authors.forename: Jin S
authors.initials: JS
authors.lastname: Ju
authors.affiliation: Department of Orofacial Pain and Oral Medicine, School of Dentistry, Yonsei University, Seoul, South Korea. Electronic address: K8756050@yuhs.ac.
authors.forename: Seong T
authors.initials: ST
authors.lastname: Kim
authors.affiliation: Oral Anatomy, School of Dentistry, Kyungpook National University, Daegu, South Korea. Electronic address: ycbae@knu.ac.kr.
authors.forename: Yong C
authors.initials: YC
authors.lastname: Bae
authors.affiliation: Department of Oral Physiology, School of Dentistry, Kyungpook National University, Daegu, South Korea. Electronic address: dkahn@knu.ac.kr.
authors.forename: Dong K
authors.initials: DK
authors.lastname: Ahn
mesh_terms: D027322:Amino Acid Transport System X-AG / Q000037:antagonists & inhibitors*; D000818:Animals; D001224:Aspartic Acid / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D001253:Astrocytes / Q000187:drug effects; D019274:Botulinum Toxins, Type A / Q000494:pharmacology; D005157:Facial Pain / Q000188:drug therapy*; D005620:Freund's Adjuvant / Q000037:antagonists & inhibitors / Q000494:pharmacology; D005974:Glutamate-Ammonia Ligase / Q000037:antagonists & inhibitors; D018698:Glutamic Acid / Q000378:metabolism*; D006930:Hyperalgesia / Q000139:chemically induced / Q000188:drug therapy*; D007276:Injections, Intraventricular; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008297:Male; D008717:Methionine Sulfoximine / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D059225:Nociception / Q000187:drug effects*; D051381:Rats; D066148:Spinal Cord Dorsal Horn / Q000187:drug effects / Q000502:physiology
chemical_list: D027322:Amino Acid Transport System X-AG; D053583:Interleukin-1beta; C120673:benzyloxyaspartate; D008717:Methionine Sulfoximine; D001224:Aspartic Acid; D018698:Glutamic Acid; D005620:Freund's Adjuvant; D019274:Botulinum Toxins, Type A; D005974:Glutamate-Ammonia Ligase
keywords: Glutamate; Glutamate transporter; Glutamine synthetase inhibitor; Orofacial pain; Paradoxical antinociception