title: Modulation of spinal nociception by GluR5 kainate receptor ligands in acute and hyperalgesic states and the role of gabaergic mechanisms.
abstract: GluR5 receptors modulate spinal nociception, however, their role in nociceptive hypersensitivity remains unclear. Using behavioural and electrophysiological approaches, we have investigated several GluR5 ligands in acute and hyperalgesic states. Furthermore, as the GABAergic system plays a role in GluR5 mediated effects in the brain, we also analysed the interaction between GluR5 agonists and GABA(A) antagonists in the spinal cord. In young rats in vivo, the GluR5 selective agonist ATPA was antinociceptive and antihyperalgesic in a model of inflammatory hyperalgesia (ED(50) approximately 4.6 and approximately 5.2 mg/kg, respectively), whereas the GluR5/GluR6 agonist SYM2081 was only antihyperalgesic. ATPA, but not SYM2081, was also able to inhibit nociceptive motoneurone responses in anaesthetised adult rats after intrathecal administration. In hemisected spinal cords in vitro, SYM2081 was inactive, whereas ATPA and another GluR5 agonist, (S)-5-iodowillardiine, inhibited nociceptive reflexes (EC(50) 1.1+/-0.4 micro M and 0.36+/-0.05 micro M, respectively). Both GluR5 agonists also inhibited motoneurone responses to repetitive dorsal root stimulation and their cumulative depolarisation, a correlate of wind-up. The GABA(A) antagonists bicuculline (10 micro M) and SR95531 (1 micro M) enhanced polysynaptic responses to single stimuli but abolished the cumulative depolarisation. Both bicuculline and SR95531 significantly attenuated the inhibition of nociceptive responses by 1 micro M ATPA (by approximately 50%). We conclude that selective GluR5 kainate receptor activation inhibits spinal nociception and its sensitisation caused by ongoing peripheral nociceptive drive. GABA(A) receptors are involved in tonic inhibition of segmental responses, but contribute to their sensitisation by repetitive primary afferent stimulation. Furthermore, there is a cross-talk between the two systems, presumably due to GluR5-mediated activation of GABAergic inhibitory interneurones in the spinal cord.
authors.affiliation: Department of Pharmacology, Grünenthal GmbH Research and Development, Zieglerstrasse 6, D-52078, Aachen, Germany.
authors.forename: Paula
authors.initials: P
authors.lastname: Mascias
authors.forename: Manuela
authors.initials: M
authors.lastname: Scheede
authors.forename: Petra
authors.initials: P
authors.lastname: Bloms-Funke
authors.forename: Boris
authors.initials: B
authors.lastname: Chizh
mesh_terms: D000758:Anesthesia; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D001640:Bicuculline / Q000494:pharmacology; D004558:Electric Stimulation; D004594:Electrophysiology; D005260:Female; D018756:GABA Antagonists / Q000494:pharmacology; D005971:Glutamates / Q000494:pharmacology; D006930:Hyperalgesia / Q000503:physiopathology*; D007395:Interneurons / Q000502:physiology; D008024:Ligands; D008297:Male; D009046:Motor Neurons / Q000187:drug effects / Q000502:physiology; D018482:Muscle, Skeletal / Q000187:drug effects / Q000502:physiology; D009619:Nociceptors / Q000187:drug effects / Q000502:physiology*; D011724:Pyridazines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018092:Kainic Acid Receptors / Q000037:antagonists & inhibitors / Q000187:drug effects*; D013116:Spinal Cord / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000502:physiology*
chemical_list: D001640:Bicuculline; D018756:GABA Antagonists; D005971:Glutamates; D008024:Ligands; D011724:Pyridazines; D018092:Kainic Acid Receptors; D005680:gamma-Aminobutyric Acid; C046105:4-methylglutamic acid; C049853:gabazine