Spinal cord mechanisms mediating behavioral hyperalgesia induced by neurokinin-1 tachykinin receptor activation in the rostral ventromedial medulla.

Abstract

Hyperalgesia in animal injury models is linked to activation of descending raphespinal modulatory circuits originating in the rostral ventromedial medulla (RVM). A neurokinin-1 (NK-1) receptor antagonist microinjected into the RVM before or after inflammation produced by complete Freund's adjuvant (CFA) resulted in an attenuation of thermal hyperalgesia. A transient (acute) or a continuous infusion of Substance P (SP) microinjected into the RVM of non-inflamed animals led to similar pain hypersensitivity. Intrathecal pretreatment or post-treatment of a 5-HT3 receptor antagonist (Y-25130 or ondansetron) blocked the SP-induced hyperalgesia. The SP-induced hyperalgesia was both GABA(A) and NMDA receptor-dependent after pre- and post-treatment with selective antagonists at the spinal level. A microinjection of SP into the RVM also led to increased NMDA NR1 receptor subunit phosphorylation in spinal cord tissue. The GABA(A) receptor-mediated hyperalgesia involved a shift in the anionic gradient in dorsal horn nociceptive neurons and an increase in phosphorylated NKCC1 protein (isoform of the Na-K-Cl cotransporter). Following a low dose of SP infused into the RVM, intrathecal muscimol (GABA(A) agonist) increased SP-induced thermal hyperalgesia, phosphorylated NKCC1 protein expression, and NMDA NR1 subunit phosphorylation in the spinal cord. The thermal hyperalgesia was blocked by intrathecal gabazine, the GABA(A) receptor antagonist, and MK-801, the NMDA receptor channel blocker. These findings indicate that NK-1 receptors in the RVM are involved in SP-induced thermal hyperalgesia, this hyperalgesia is 5-HT3-receptor dependent at the spinal level, and involves the functional interaction of spinal GABA(A) and NMDA receptors.

• Authors: S C Lagraize, W Guo, K Yang, F Wei, K Ren, R Dubner
• Journal: Neuroscience (Neuroscience) Vol. 171 Issue 4 Pg. 1341-56 (Dec 29 2010) ISSN: 1873-7544 [Electronic] United States
• PMID: 20888891 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2010. Published by Elsevier Ltd.

Chemical References

• Bridged Bicyclo Compounds, Heterocyclic
• Excitatory Amino Acid Antagonists
• GABA Agents
• Oxazines
• Pyridazines
• Receptors, Neurokinin-1
• Serotonin Antagonists
• 3,5-bis(trifluoromethyl)benzyl N-acetyltryptophan
• Muscimol
• Substance P
• Ondansetron
• Dizocilpine Maleate
• azasetron
• Tryptophan
• Freund's Adjuvant
• gabazine

Topics

• Animals
• Behavior, Animal
• Bridged Bicyclo Compounds, Heterocyclic (pharmacology)
• Disease Models, Animal
• Dizocilpine Maleate (pharmacology)
• Dose-Response Relationship, Drug
• Drug Administration Schedule
• Drug Interactions
• Excitatory Amino Acid Antagonists (pharmacology)
• Freund's Adjuvant
• GABA Agents (pharmacology)
• Hyperalgesia (etiology, pathology, prevention & control)
• In Vitro Techniques
• Inflammation (chemically induced, complications)
• Male
• Medulla Oblongata (drug effects, metabolism)
• Membrane Potentials (drug effects)
• Microinjections (methods)
• Muscimol (pharmacology)
• Ondansetron (pharmacology)
• Oxazines (pharmacology)
• Pain Measurement
• Pain Threshold (drug effects, physiology)
• Posterior Horn Cells (drug effects, physiology)
• Pyridazines (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Reaction Time (drug effects, physiology)
• Receptors, Neurokinin-1 (metabolism)
• Serotonin Antagonists (pharmacology)
• Spinal Cord (cytology, metabolism)
• Substance P (pharmacology)
• Tryptophan (analogs & derivatives, pharmacology)
• Up-Regulation (drug effects)