NK3 receptor blockade prevents hyperalgesia and the associated spinal cord substance P release in monoarthritic rats.

Abstract

Previous studies in vitro have shown that NK3 receptors exist on primary afferent terminals in rat spinal cord and mediate potentiation of the depolarisation-evoked substance P (SP) release. In the present study we have investigated the role of the NK3 receptor-mediated SP release system in a model of inflammatory pain. Monoarthritis was induced in rats by unilateral injection of complete Freund's adjuvant (CFA); withdrawal latencies to a thermal stimulus were subsequently measured at various times following CFA. The CFA-treated paw displayed hyperalgesia as early as 4 h after CFA injection and hyperalgesia was maintained until day 4 but had disappeared by day 21. The thermal hyperalgesia was associated with an increase in basal SP release from spinal cord synaptosomes. The possible involvement of endogenous neurokinin B acting at NK3 receptors was tested by using SB 223412-A [(S)-(-)-N-(alpha-ethylbenzyl)-3-hydroxy-2-phenylquinoline-4-carbo xamide hydrochloride], a novel, potent (Ki=30 nM) and selective (Ki>10,000 nM for NK1 and NK2 receptors), non-peptidic NK3 receptor antagonist. In vitro SB 223412-A antagonised the potentiation of SP release produced by senktide in spinal cord synaptosomes. Administered systemically to monoarthritic rats (50 mg/kg, p.o., b.i.d., for 4 days), the NK3 receptor antagonist SB 223412-A significantly reduced thermal hyperalgesia and normalised the basal release of SP from spinal cord synaptosomes. The data suggest that neurokinin B acting at NK3 receptors that mediate SP release within the spinal cord play a role in inflammation. These NK3 receptors may represent, therefore, appropriate targets in the therapy of inflammatory pain.

• Authors: P Zaratin, O Angelici, G D Clarke, G Schmid, M Raiteri, F Carità, G Bonanno
• Journal: Neuropharmacology (Neuropharmacology) Vol. 39 Issue 1 Pg. 141-9 ( 2000) ISSN: 0028-3908 [Print] England
• PMID: 10665827 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Peptide Fragments
• Quinolines
• Receptors, Neurokinin-3
• senktide
• SB 223412
• Substance P
• Freund's Adjuvant

Topics

• Afferent Pathways (physiology)
• Animals
• Arthritis, Experimental (physiopathology)
• Freund's Adjuvant
• Hyperalgesia (physiopathology)
• Inflammation
• Male
• Pain (physiopathology)
• Peptide Fragments (pharmacology)
• Quinolines (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Reaction Time
• Receptors, Neurokinin-3 (antagonists & inhibitors)
• Spinal Cord (physiology, physiopathology)
• Substance P (analogs & derivatives, metabolism, pharmacology, physiology)