Transient, 5-HT2B receptor-mediated facilitation in neuropathic pain: Up-regulation of PKCγ and engagement of the NMDA receptor in dorsal horn neurons

Autor: Manfred Zimmermann, Itsaso Buesa, Juan Bilbao, Francisco Doñate, Gontzal García del Caño, Jon Jatsu Azkue, Zigor Aira
Rok vydání: 2013
Předmět:
Agonist
Male
medicine.medical_specialty
Indoles
Time Factors
medicine.drug_class
SB-204741
Thiophenes
Receptors
N-Methyl-D-Aspartate
Rats
Sprague-Dawley
chemistry.chemical_compound
Postsynaptic potential
Internal medicine
Physical Stimulation
Receptor
Serotonin
5-HT2B
medicine
Animals
Humans
Enzyme Inhibitors
Evoked Potentials
Protein Kinase C
Neurons
Nerve Fibers
Unmyelinated
Dose-Response Relationship
Drug
Chemistry
Glutamate receptor
Rats
Serotonin Receptor Agonists
Up-Regulation
Disease Models
Animal
Anesthesiology and Pain Medicine
Nociception
Endocrinology
HEK293 Cells
Spinal Nerves
nervous system
Neurology
Hyperalgesia
Neuropathic pain
Synaptic plasticity
NMDA receptor
Neuralgia
Neurology (clinical)
Spinal Nerve Roots
Neuroscience
Excitatory Amino Acid Antagonists
Subcellular Fractions
Zdroj: PainReferences. 154(9)
ISSN: 1872-6623
Popis: Spinal nociception can be facilitated by 5-HT2 receptors in neuropathic pain. We investigated the involvement of glutamate receptors in dorsal neuron hyperexcitation that is promoted by 5-HT2B receptor (5-HT2BR) after spinal nerve ligation (SNL) in the rat. Augmentation of C-fiber-evoked potentials by spinal superfusion with 5-HT2BR agonist BW 723C86 in nerve-ligated rats was impeded by co-administration of NMDA receptor (NMDAR) antagonist D-AP5, but not by mGluR1/5 antagonist AIDA or mGluR2/3 antagonist LY 341495. Evoked potentials were increased by cis-ACPD in nerve-injured rats, irrespective of simultaneous 5-HT2BR blockade by SB204741. In uninjured rats, NMDAR agonist cis-ACPD enhanced evoked potentials in the presence of BW 723C86 but not if administered alone or during exposure to protein kinase C γ (PKCγ) inhibitor peptide. Triple immunofluorescence labelings revealed co-localization of NMDAR and 5-HT2BR in PKCγ-expressing perikarya in lamina II neurons. As a result of SNL, PKCγ was transiently and bilaterally up-regulated in synaptic fraction from dorsal horn homogenates, peaking at day 2 and returning to basal levels by day 9. Chronic blockade of 5-HT2BR with selective antagonist SB 204741 after SNL bilaterally decreased the following: (i) PKCγ up-regulation in synaptic fraction, (ii) phosphorylation of NMDAR subunit NR1 (serine 889) in synaptic fraction, and (iii) co-localization of both PKCγ and phosphorylated NR1 with postsynaptic marker PSD-95. Chronic delivery of SB 204741 bilaterally attenuated thermal and mechanical allodynia occurring after SNL, particularly at day 2 post injury. These findings suggest that transient activation of the PKCγ/NMDAR pathway is critically involved in 5-HT2BR-mediated facilitation in the SNL model of neuropathic pain.
Databáze: OpenAIRE
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