title: N-Methyl-D-aspartate receptor antagonist d-AP5 prevents pertussis toxin-induced alterations in rat spinal cords by inhibiting increase in concentrations of spinal CSF excitatory amino acids and downregulation of glutamate transporters.
abstract: Recently, we found that intrathecal (i.t.) pertussis toxin (PTX) injection produces thermal hyperalgesia and is associated with increasing concentrations of excitatory amino acids (EAAs) in spinal cerebrospinal fluid (CSF) dialysates; a reduction in the antinociceptive effects of morphine and glutamate transporters (GTs) was also observed. The reduction in the morphine-induced analgesic effects is directly related to increased extracellular EAA levels, which are maintained by GTs at physiological levels. In this study, we aimed to examine the role of GT isoforms in thermal hyperalgesia, determine the EAA concentrations in CSF dialysates, and elucidate the role of N-methyl-d-aspartate (NMDA) receptors in PTX-induced reduction in the antinociceptive effects of morphine. Two i.t. catheters and one microdialysis probe were inserted into male Wistar rats: one catheter was used for PTX (1 microg) and morphine (10 microg) injection and the other was connected to an osmotic pump for NMDA receptor antagonist d-2-amino-5-phosphonopentanoic acid (d-AP5; 2 microg/h for 4 days) continuous infusion. The microdialysis probe was used to collect CSF dialysates for EAA measurements by high-performance liquid chromatography. Intrathecal morphine failed to produce antinociceptive effects in PTX-treated rats, and d-AP5 coinfusion prevented the PTX-induced reduction in the antinociceptive effect and associated downregulation of the GTs. We conclude that NMDA receptor suppression inhibits EAA excitation and reduces the morphine-induced antinociception in PTX-treated rats.
authors.affiliation: Department of Anesthesiology, Tri-Service General Hospital and National Defense Medical Center, Taipei, Taiwan.
authors.forename: Chih-Shung
authors.initials: CS
authors.lastname: Wong
authors.forename: Gong-Jhe
authors.initials: GJ
authors.lastname: Wu
authors.forename: Wu-Fu
authors.initials: WF
authors.lastname: Chen
authors.forename: Yen-Hsuan
authors.initials: YH
authors.lastname: Jean
authors.forename: Ching-Hsien
authors.initials: CH
authors.lastname: Hung
authors.forename: Chan-Shing
authors.initials: CS
authors.lastname: Lin
authors.forename: Shi-Ying
authors.initials: SY
authors.lastname: Huang
authors.forename: Zhi-Hong
authors.initials: ZH
authors.lastname: Wen
mesh_terms: D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology*; D027322:Amino Acid Transport System X-AG / Q000235:genetics / Q000378:metabolism*; D000701:Analgesics, Opioid / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D018846:Excitatory Amino Acids / Q000134:cerebrospinal fluid*; D006930:Hyperalgesia / Q000188:drug therapy / Q000378:metabolism; D007278:Injections, Spinal; D008297:Male; D017551:Microdialysis; D009020:Morphine / Q000494:pharmacology / Q000627:therapeutic use; D010147:Pain Measurement; D037342:Pertussis Toxin / Q000008:administration & dosage / Q000494:pharmacology*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D013116:Spinal Cord / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology
chemical_list: D027322:Amino Acid Transport System X-AG; D000701:Analgesics, Opioid; D018691:Excitatory Amino Acid Antagonists; D018846:Excitatory Amino Acids; D020033:Protein Isoforms; D016194:Receptors, N-Methyl-D-Aspartate; D015763:2-Amino-5-phosphonovalerate; D009020:Morphine; D037342:Pertussis Toxin