NK3 receptor blockade prevents hyperalgesia and the associated spinal cord substance P release in monoarthritic rats.
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.
Zaratin
P
P
Department of Biology, SmithKline Beecham S.p.A., Milan, Italy.
Angelici
O
O
Clarke
G D
GD
Schmid
G
G
Raiteri
M
M
Carità
F
F
Bonanno
G
G
D000344:Afferent Pathways / Q000502:physiology; D000818:Animals; D001169:Arthritis, Experimental / Q000503:physiopathology*; D005620:Freund's Adjuvant; D006930:Hyperalgesia / Q000503:physiopathology*; D007249:Inflammation; D008297:Male; D010146:Pain / Q000503:physiopathology; D010446:Peptide Fragments / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time; D018042:Receptors, Neurokinin-3 / Q000037:antagonists & inhibitors*; D013116:Spinal Cord / Q000502:physiology / Q000503:physiopathology*; D013373:Substance P / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*
D010446:Peptide Fragments; D011804:Quinolines; D018042:Receptors, Neurokinin-3; C054724:senktide; C106716:SB 223412; D013373:Substance P; D005620:Freund's Adjuvant