Blockade of spinal glutamate recycling produces paradoxical antinociception in rats with orofacial inflammatory pain

Kui Y. Yang, Jun H. Mun, Ki D. Park, Min J. Kim, Jin S. Ju, Seong T. Kim, Yong C. Bae, Dong K. Ahn

Research output: Contribution to journalArticlepeer-review

15 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)100-109
Number of pages10
JournalProgress in Neuro-Psychopharmacology and Biological Psychiatry
Volume57
DOIs
Publication statusPublished - 2015 Mar 3

Bibliographical note

Funding Information:
This research was supported by the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT & Future Planning ( 2008-0062282 and 2012M3A9B6055414 ) and Hugel Inc. (Chuncheon, Republic of Korea). We are grateful to Hugel Inc. for providing Botulax®.

Publisher Copyright:
© 2014 Elsevier Inc.

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Biological Psychiatry

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