NK3 receptor blockade prevents hyperalgesia and the associated spinal cordsubstance P release in monoarthritic rats

Previous studies in vitro have shown that NK3 receptors exist on primary af ferent terminals in rat spinal cord and mediate potentiation of the depolar isation-evoked substance P (SP) release. In the present study we have inves tigated the role of the NK3 receptor-mediated SP release system in a model of inflammatory pain. Monoarthritis was induced in rats by unilateral injec tion of complete Freund's adjuvant (CFA); withdrawal latencies to a thermal stimulus were subsequently measured at various times following CFA. The CP A-treated paw displayed hyperalgesia as early as 4 h after CFA injection an d hyperalgesia was maintained until day 4 but had disappeared by day 21, Th e thermal hyperalgesia was associated with an increase in basal SP release from spinal cord synaptosomes. The possible involvement of endogenous neuro kinin B acting at NK3 receptors was tested by using SB 223412A [(S)-(-)-N-( alpha-ethylbenzyl)-3-hydroxy-2-phenylquinoline-4-carboximide hyrochloride], a novel, potent (ki = 30 nM) and selective (K-i >10 000 nM for NK1 and NK2 receptors), non-peptidic NK3 receptor antagonist. In vitro SB 223412-A ant agonised 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 significa ntly reduced thermal hyperalgesia and normalised the basal release of SP fr om spinal cord synaptosomes. The data suggest that neurokinin B acting at N K, receptors that mediate SP release within the spinal cord play a role in inflammation. These NK3 receptors may represent, therefore, appropriate tar gets in the therapy of inflammatory pain. (C) 1999 Elsevier Science Ltd. Al l rights reserved.