Presynaptic low- and high-affinity kainate receptors in nociceptive spinal afferents

Lucifora, Simona; Willcockson, Helen H.; Lu, Chun Rong; Darstein, Melanie; Phend, Kristen D.; Valtschanoff, Juli G.; Rustioni, Aldo

doi:10.1016/j.pain.2005.10.018

Cited by 33 publications

(37 citation statements)

References 75 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…11e The location of GluK1 on the non-peptidergic population of nociceptive afferents led to the hypothesis that GluK1 antagonists might be effective modulators of neuropathic, as opposed to inflammatory pain. 31 Likewise, GluN2D-containing receptors have a specific role in neuropathic pain; GluN2D knockout mice do not display enhanced pain responses in the sciatic nerve ligation model. 4b Hence, a dual GluK1/GluN2D selective agent would be predicted to have enhanced antinociceptive properties.…”

Section: Discussionmentioning

confidence: 99%

Piperazine-2,3-dicarboxylic Acid Derivatives as Dual Antagonists of NMDA and GluK1-Containing Kainate Receptors

et al. 2011

View full text Add to dashboard Cite

Competitive N-methyl-D-aspartate receptor (NMDAR) antagonists bind to the GluN2 subunit, of which there are four types (GluN2A-D). We report that some N1-substituted derivatives of cis-piperazine-2,3-dicarboxylic acid display improved relative affinity for GluN2C and GluN2D versus GluN2A and GluN2B. These derivatives also display subtype-selectivity among the more distantly related kainate receptor family. Compounds 18i and (−)-4 were the most potent kainate receptor antagonists and 18i was selective for GluK1 versus GluK2, GluK3 and AMPA receptors. Modeling studies revealed structural features required for activity at GluK1 subunits and suggested that S674 was vital for antagonist activity. Consistent with this hypothesis, replacing the equivalent residue in GluK3 (alanine) with a serine imparts 18i antagonist activity. Antagonists with dual GluN2D and GluK1 antagonist activity may have beneficial effects in various neurological disorders. Consistent with this idea, antagonist 18i (30 mg/Kg i.p.) showed antinociceptive effects in an animal model of mild nerve injury.

show abstract

Section: Discussionmentioning

confidence: 99%

Piperazine-2,3-dicarboxylic Acid Derivatives as Dual Antagonists of NMDA and GluK1-Containing Kainate Receptors

et al. 2011

View full text Add to dashboard Cite

show abstract

“…The question on the possibility of involvement of kainate receptors in transmission from primary afferents remains open. Subunits of these receptors are present in a majority of postsynaptic structures in the dendrites of DH neurons [23,24], but such subunits are mostly of a cytoplasmic nature and are not activated during the main events of synaptic transmission [24]. Thus, glutamatergic neurotransmission in synapses of DRG neurons on DH neurons under our co-culturing conditions is mostly mediated by activation of postsynaptic AMPA receptors.…”

Section: Discussionmentioning

confidence: 94%

Induction of Long-Term Depression of Synaptic Transmission in a Co-Culture of DRG and Spinal Dorsal Horn Neurons of Rats

2011

View full text Add to dashboard Cite

In a co-culture of dissociated neurons of lumbar dorsal root ganglia (DRG) and spinal dorsal horn (DH) neurons of newborn rats, we examined peculiarities of induction of long-term depression (LTD) of synaptic transmission through synapses formed by primary afferents on DH neurons. Induction of LTD was provided by low-frequency (5 sec -1 ) microstimulation of single DRG neurons. Ion currents were simultaneously recorded in pre-and post-synaptic cells using a dual whole-cell path-clamp technique. Parameters of evoked excitatory and inhibitory postsynaptic currents (eEPSCs and eIPSCs, respectively) initiated in DH neurons by intracellular stimulation of DRG neurons were analyzed. Monosynaptic eEPSC mediated by activation of AMPA receptors demonstrated no sensitivity to blockers of NMDA and kainate receptors (20 μM D L -AP5 and 10 μM SIM 2081, respectively), but were entirely blocked upon applications of 10 μM DNQX. Monosynaptic glycinergic eIPSCs found in some of the DH neurons were blocked by 1 μM strychnine and were insensitive to 10 μM bicuculline and blockers of glutamatergic neurotransmission, D L -AP5 and DNQX. Long-lasting (360 sec) low-frequency stimulation of DRG neurons did not affect the amplitude of glycineinduced eIPSCs in DH neurons. At the same time, such stimulation of DRG neurons evoked a drop in the amplitude of AMPA-activated eEPSCs in DH neurons to 41.6 ± 2.5%, on average, as compared with the analogous index in the control. This effect lasted at least 20 min after stimulation. Long-term depression of glutamatergic transmission in DH neurons was observed at the holding potential of -70 mV and did not change after applications of 10 μM bicuculline and 1 μM strychnine. The LTD intensity depended on the duration of low-frequency stimulation of primary afferent neurons. Sequential stimulation of DRG neurons lasting 120, 160, 200, and 240 sec resulted in decreases in the eEPSC amplitude in DH neurons to 85.6 ± 3.9, 62.7 ± 4.3, 51.8 ± 3.5, and 41.6 ±2.5% with respect to control values. Our findings show that use-dependent induction of homosynaptic LTD of glutamatergic transmission is possible at the level of a separate pair of synaptically connected DRG and DH neurons under co-culturing conditions. Such LTD of glutamatergic synaptic transmission mostly mediated by activation of AMPA receptors depends on the duration of activation of a presynaptic DRG neuron and does not need depolarization of a postsynaptic DH neuron.Keywords: synaptic transmission, long-term depression, dorsal root ganglion (DRG) neurons, neurons of the dorsal horn (DH) of the spinal cord, co-culture, glutamate, glycine.

show abstract

“…The presence of kainite receptors with both low and high affinities within the DRG could be the reason for the development of the broad and progressive concentration-based changes in nociception related to UBP-301 concentration. [22]…”

Section: Discussionmentioning

confidence: 99%

The utility of ionotropic glutamate receptor antagonists in the treatment of nociception induced by epidural glutamate infusion in rats

Osgood

Harrington²,

Kenney³

et al. 2013

Surg Neurol Int

View full text Add to dashboard Cite

Background:The authors have previously demonstrated that human herniated disc material contains high concentrations of free glutamate. In an experimental model, elevated epidural glutamate concentrations in the lumbar spine can cause a focal hyperesthetic state.Methods:Rats underwent epidural glutamate infusion in the lumbar spine by a miniosmotic pump over a 72-hour period. Some rats underwent coinfusion with glutamate and ionotropic glutamate antagonists. Nociception was assessed by von Frey fibers and by assessment of glutamate receptor expression in the corresponding dorsal horn of the spinal cord.Results:The kainic acid antagonist, UBP 301, decreased epidural glutamate-based hyperesthesia in a dose dependent manner. Concordant with these findings, there was significant decrease in kainate receptor expression in the dorsal horn. The N-Methyl-4-isoxazoleproionic acid (NMDA) antagonist Norketamine also significantly diminished hyperesthesia and decreased receptor expression in the dorsal horn.Conclusions:Both UBP 301, the kainic acid receptor antagonist and Norketamine, an NMDA receptor antagonist, dampened epidural glutamate-based nociception. Focal epidural injections of Kainate or NMDA receptor antagonists could be effective treatments for disc herniation-based lumbar radiculopathy.

show abstract

Presynaptic low- and high-affinity kainate receptors in nociceptive spinal afferents

Cited by 33 publications

References 75 publications

Piperazine-2,3-dicarboxylic Acid Derivatives as Dual Antagonists of NMDA and GluK1-Containing Kainate Receptors

Piperazine-2,3-dicarboxylic Acid Derivatives as Dual Antagonists of NMDA and GluK1-Containing Kainate Receptors

Induction of Long-Term Depression of Synaptic Transmission in a Co-Culture of DRG and Spinal Dorsal Horn Neurons of Rats

The utility of ionotropic glutamate receptor antagonists in the treatment of nociception induced by epidural glutamate infusion in rats

Contact Info

Product

Resources

About