Studies on the vascular permeability induced by intrathecal substance P and bradykinin in the rat

The effects of substance P (SP), SP fragments, neurokinin A (NKA), neurokinin B (NKB) and selective agonists for neurokinin receptors were assessed on cutaneous vascular permeability after intrathecal (i.t.) administration in rats. Dose-dependent increases in plasma extravasation were observed with the following rank orders of potency ([p-Glu6]SP-(6-11) greater than SP greater than or equal to SP-(4-11) greater than [p-Glu5,MePhe8,Sar9]SP-(5-11) = [p-Glu5]SP-(5-11) greater than SP-(7-11) and SP greater than NKA greater than NKB). The N-terminal fragments SP-(1-4), SP-(1-7) and SP-(1-9) were inactive up to 65 nmol. The NK-1 receptor selective agonists [( beta-Ala4,Sar9,Met(O2)11]SP-(4-11) and [Pro9,Met(O2)11]SP) were more potent than the NK-2 ([Nle10]NKA-(4-10] and NK-3 ([beta-Asp4,MePhe7]NKB-(4-10) and [MePhe7]NKB) receptor-selective agonists. Plasma extravasation was also increased by i.t. bradykinin (BK, 8.1 nmol) while the fragment BK-(1-8), a potent B1-receptor-selective agonist, produced only a slight effect at 81 nmol. When BK was given after prior i.t. administration of 6.1 nmol of [Thi5.8,D-Phe7]BK, an antagonist of BK at the B2-receptor, the increase in vascular permeability was significantly attenuated. The analogue [Leu8]BK-(1-8) (10.3 nmol), an antagonist of BK at the B1-receptor, failed to modify the BK-induced plasma extravasation. Plasma extravasation induced by SP (6.5 nmol) and BK (8.1 nmol) was abolished in cervically vagotomized rats, and significantly reduced in both spinal rats and in capsaicin-treated animals. Conversely, bilateral adrenalectomy (48 h earlier) and intercollicular decerebration (30 min earlier) had no major effect on the response elicited either by SP or BK. The response to SP remained unaffected by methysergide and hexamethonium but was significantly reduced by methylnitrate atropine and diphenhydramine. Indomethacin significantly enhanced the plasma extravasation induced by SP. These results suggest that SP and BK may play a role as spinal mediators in peripheral vascular permeability through a sensory and cholinergic vagal mechanism involving a spinobulbar pathway. The receptors mediating the response to SP and BK in the spinal cord are of the NK-1 and B2 subtypes, respectively.