title: The antinociceptive effect of SNAP5114, a gamma-aminobutyric acid transporter-3 inhibitor, in rat experimental pain models.
abstract: BACKGROUND
  Gamma-aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in the mammalian central nervous system. GABAergic transmission has an important role in regulating nociception at the spinal dorsal horn. It is terminated by rapid uptake of the neurotransmitter from the synaptic cleft into neurons and glial cells, via specific GABA transporters (GATs). Among the 4 GATs, GAT-3 has the greatest expression in central nervous system regions closely associated with nociceptive transmission, including the spinal cord. In this study, we examined the antinociceptive effect of intrathecal administration of a selective GAT-3 inhibitor, SNAP5114, on acute, inflammatory, and neuropathic pain in experimental models.
  
  
  METHODS
  Male Sprague-Dawley rats were used to assess thermal, mechanical, and chemical nociception in the tail flick and hotplate tests, the paw pressure test, and the formalin test. A rotarod test was performed to assess motor function. Chronic constriction injury to the sciatic nerve was induced in the rats. The electronic von Frey test and the plantar test were then performed to assess mechanical allodynia and thermal hyperalgesia. SNAP5114 (10, 50, 100, or 200 μg) was administered intrathecally to examine antinociceptive activity. To confirm whether the action of SNAP5114 was mediated by GABAergic transmission, the GABAA receptor antagonist bicuculline (0.3 μg) or the GABAB receptor antagonist CGP35348 (30 μg) was administered intrathecally before 200 μg of SNAP5114 in the tail flick test, the formalin test, and the electronic von Frey test.
  
  
  RESULTS
  Spinally applied SNAP5114 in normal rats dose-dependently prolonged withdrawal latencies in the tail flick test and suppressed the late-phase response in the formalin test. SNAP5114 did not affect motor performance. In the chronic constriction injury rats, SNAP5114 inhibited mechanical allodynia dose-dependently. The antinociceptive action of SNAP5114 was partially reversed by bicuculline or CGP35348 at doses at which the antagonist alone did not affect baseline behavioral responses.
  
  
  CONCLUSIONS
  These results suggest that SNAP5114 exerts antinociceptive effects by activating GABAA and GABAB receptors in the spinal cord. The GAT-3 inhibitor may prove useful in treatment of various painful conditions.
authors: From the Department of Anesthesiology, University of Occupational and Environmental Health, School of Medicine, Kitakyushu, Japan.
authors: Kazunori
authors: K
authors: Kataoka
authors: Koji
authors: K
authors: Hara
authors: Yasunori
authors: Y
authors: Haranishi
authors: Tadanori
authors: T
authors: Terada
authors: Takeyoshi
authors: T
authors: Sata
mesh_terms: D059787:Acute Pain / Q000188:drug therapy; D000700:Analgesics; D000818:Animals; D000840:Anisoles / Q000494:pharmacology* / Q000627:therapeutic use; D001522:Behavior, Animal / Q000187:drug effects; D059350:Chronic Pain / Q000188:drug therapy; D003251:Constriction, Pathologic / Q000150:complications / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D005502:Food; D005557:Formaldehyde; D018756:GABA Antagonists / Q000494:pharmacology; D050485:GABA Plasma Membrane Transport Proteins / Q000187:drug effects*; D006358:Hot Temperature; D007278:Injections, Spinal; D008297:Male; D009557:Nipecotic Acids / Q000494:pharmacology* / Q000627:therapeutic use; D010146:Pain / Q000188:drug therapy*; D010147:Pain Measurement / Q000187:drug effects; D010812:Physical Stimulation; D004856:Postural Balance / Q000187:drug effects; D011312:Pressure; D011597:Psychomotor Performance / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects
chemical_list: C092337:1-(2-(tris(4-methoxyphenyl)methoxy)ethyl)-3-piperidinecarboxylic acid; D000700:Analgesics; D000840:Anisoles; D018756:GABA Antagonists; D050485:GABA Plasma Membrane Transport Proteins; D009557:Nipecotic Acids; C493417:Slc6a11 protein, rat; D005557:Formaldehyde