Modulation of spinal nociception by GluR5 kainate receptor ligands in acute and hyperalgesic states and the role of gabaergic mechanisms

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 G...

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Published in:	Neuropharmacology Vol. 43; no. 3; pp. 327 - 339
Main Authors:	Mascias, Paula, Scheede, Manuela, Bloms-Funke, Petra, Chizh, Boris A
Format:	Journal Article
Language:	English
Published:	Oxford Elsevier Ltd 01-09-2002 Elsevier
Subjects:	Anesthesia Animals Behavior, Animal - drug effects Behavior, Animal - physiology Bicuculline - pharmacology Biological and medical sciences Electric Stimulation Electrophysiology Female Fundamental and applied biological sciences. Psychology GABA A receptors GABA Antagonists - pharmacology gamma-Aminobutyric Acid - physiology Glutamates - pharmacology Hyperalgesia Hyperalgesia - physiopathology Inflammation Interneurons - physiology Kainate receptors Ligands Male Motor Neurons - drug effects Motor Neurons - physiology Muscle, Skeletal - drug effects Muscle, Skeletal - physiology Nociception Nociceptors - drug effects Nociceptors - physiology Pyridazines - pharmacology Rats Rats, Sprague-Dawley Receptors, Kainic Acid - antagonists & inhibitors Receptors, Kainic Acid - drug effects Somesthesis and somesthetic pathways (proprioception, exteroception, nociception); interoception; electrolocation. Sensory receptors Spinal cord Spinal Cord - physiology Vertebrates: nervous system and sense organs Nociception Spinal cord Kainate receptors Inflammation GABA A receptors Hyperalgesia Primary afferent depolarization mglu5 glutamate receptor Rat Hypersensitivity Rodentia Central nervous system Hyperalgesia: Inflammation Interneuron Kainate receptor Gabaergic pathway Vertebrata Mammalia Animal Sensory neuron Mechanism of action Gabaergic receptor A GABAA receptors
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Summary:	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 ~4.6 and ~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 μM and 0.36±0.05 μM, 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 μM) and SR95531 (1 μM) enhanced polysynaptic responses to single stimuli but abolished the cumulative depolarisation. Both bicuculline and SR95531 significantly attenuated the inhibition of nociceptive responses by 1 μM ATPA (by ~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.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 ObjectType-Article-1 ObjectType-Feature-2
ISSN:	0028-3908 1873-7064
DOI:	10.1016/S0028-3908(02)00112-0