Priming effects of substance P on calcium changes evoked by interleukin-8 in human neutrophils

The neurokinin (NK) substance P (SP), which is a mediator of neurogenic inflammation, has been reported to prime human polymorphonuclear neutrophils (PMNs). The priming effects of SP on PMNs activated by recombinant interleukin-8 (rIL-8) were investigated. SP enhanced, in a dose- and time-dependent way, the rise in cytosolic free-calcium concentration, [Ca(2+)]i, evoked by the chemokine. The priming effects of SP were abolished by exposing PMNs to a calcium-free medium supplemented with EGTA. The C-terminal peptides SP(4-11) and SP(6-11) but not the N-terminal peptide SP(1-7) shared the priming effects of SP. The selective NK-1 receptor agonist [Sar-9, MetO2-11]SP mimicked the effects of SP, which were not reproduced by the selective NK-2 receptor agonist [betaAla-8]-NKA(4-10) or the selective NK-3 agonist senktide. Two selective NK-1 antagonists, CP96,345 and L703,606, dose dependently inhibited SP priming effects. These results demonstrated that SP primes PMNs exposed to rIL-8 and suggested that SP priming effects are receptor mediated.     

The effects of substance P on neuromuscular transmission in the frog

The effects of substance P (SP) on cholinergic transmission were studied at the neuromuscular junction of frogs by intracellular and voltage-clamp recording methods. Bath application of SP increased the amplitude of end-plate potential (e.p.p.) evoked in either low-Ca2+ -high Mg2+ or curare-containing solution. SP at a concentration of 0.1-1 microM produced a dose-dependent increase in the quantal content of the e.p.p., while having no significant effects on the quantal size. The frequency of m.e.p.p. was increased by SP. SP (1 microM) did not change the sensitivity of nicotinic receptors at the end-plate. These results suggest that SP presynaptically facilitates the neuromuscular transmission, increasing the evoked release of ACh from motor nerve terminals.     

神经肽K物质,P物质对小鼠脾脏和胸腺淋巴细胞的影响

研究了速激肽SK和SP对小鼠脾脏和胸腺淋巴细胞的作用,观察到SK与SP在亚适量的ConA或LPS共同作用下,能促进脾脏细胞的体外增殖和抗体生成。此外,5×10~(-7)M的SK对ConA激活的胸腺细胞有促增殖作用,而SP没有这个效应。FACS分析的结果表明,SK能促使ConA激活的脾脏和胸腺T淋巴细胞亚群发生变化,使脾脏细胞中lyt2~ 细胞所占比例上升,而L_3T_4~ 细胞比例不变;使胸腺细胞lyt 2~ 和L_4~ 比例都下降。以上结果表明神经肽SK、SP对免疫反应有调节作用。     

Antagonism of non-cholinergic excitatory junction potentials in the guinea-pig ileum by a substance P analogue antagonist

In the presence of atropine electrical transmural stimulation (using repetitive volleys, e.g. 3 pulses at 50 Hz applied every 4 s) of full thickness longitudinal strips of guinea-pig ileum produced non-cholinergic excitatory junction potentials (EJPs) and inhibitory junction potentials (IJPs) in the circular muscle layer. After abolition of the IJPs with apamin, the non-cholinergic EJPs clearly showed facilitation. In the presence of apamin and the substance P analogue antagonist, [D-Arg1,D-Pro2,D-Trp7-9,Leu11]-substance P (SPA), the non-cholinergic EJPs were reduced by 60-90%; transmural stimulation now revealed an apamin-resistant IJP followed by a slow depolarization. The atropine-resistant EJPs are probably caused by the release of substance P (or a similar compound) and are likely to underlie the non-cholinergic contractions reported to occur in this tissue.     

Electrophysiological effects of substance P and VIP in the denervated rat parotid gland

The effects of SP and VIP were studied in vitro in normal and denervated parotid glands of the rat using electrophysiological techniques. After sympathetic, and especially after parasympathetic, denervation the number of cells responding to peptides increased significantly. Furthermore, sub-threshold doses for control glands induced membrane potential changes after denervation. It seems reasonable to correlate these findings to the development of supersensitivity. The underlying mechanisms, however, require further investigation.     

Probing the effects of stress mediators on the human hair follicle: substance P holds central position

Stress alters murine hair growth, depending on substance P-mediated neurogenic inflammation and nerve growth factor (NGF), a key modulator of hair growth termination (catagen induction). Whether this is of any relevance in human hair follicles (HFs) is completely unclear. Therefore, we have investigated the effects of substance P, the central cutaneous prototypic stress-associated neuropeptide, on normal, growing human scalp HFs in organ culture. We show that these prominently expressed substance P receptor (NK1) at the gene and protein level. Organ-cultured HFs responded to substance P by premature catagen development, down-regulation of NK1, and up-regulation of neutral endopeptidase (degrades substance P). This was accompanied by mast cell degranulation in the HF connective tissue sheath, indicating neurogenic inflammation. Substance P down-regulated immunoreactivity for the growth-promoting NGF receptor (TrkA), whereas it up-regulated NGF and its apoptosis- and catagen-promoting receptor (p75NTR). In addition, MHC class I and beta2-microglobulin immunoreactivity were up-regulated and detected ectopically, indicating collapse of the HF immune privilege. In conclusion, we present a simplistic, but instructive, organ culture assay to demonstrate sensitivity of the human HF to key skin stress mediators. The data obtained therewith allow one to sketch the first evidence-based biological explanation for how stress may trigger or aggravate telogen effluvium and alopecia areata.     

P物质及其免疫调节作用的研究进展

神经肽P物质(SP)是神经内分泌免疫网络中的重要一员,广泛分布于中枢和周围神经系统及组织器官.SP主要通过与细胞表面的相应神经激肽受体(NKR)结合介导其生物学活性,其中SP与NKR-1结合的亲和力最高,NKR-1广泛分布于各种免疫细胞,SP以神经内分泌的方式作用于各种免疫细胞,参与免疫调节.SP既可影响非特异性免疫,也可影响特异性免疫反应.     

Neuronal substance P in the esophagus. Distribution and effects on motor activity

Substance P-immunoreactive nerve fibres were fairly numerous in the lower esophagus of the guinea-pig and cat but few in the pig. They were particularly numerous in the myenteric and submucosal plexuses but could be detected also in the circular and longitudinal smooth muscle and in the muscularis mucosae. Only in the cat were SP-immunoreactive cell bodies detected, albeit in low number, in the myenteric plexus. Radioimmunoassay showed that the lower part of the cat esophagus contained approximately 10 times more immunoreactive SP than the upper part and that the muscle layer contained more SP than the mucosa. Motor effects of synthetic SP were studied on segments from circular smooth muscle of cat esophagus. SP contracted the smooth muscle and enhanced the response to electrical stimulation. These effects of SP could be blocked by the specific SP antagonist (d -Pro,²d -Trp^7,8)-SP. The contractile response to electrical stimulation could be blocked by the cholinergic muscarinic blocker atropine and the opiate receptor agonist leu-enkephalin but not by the SP antagonist or by adrenergic blockers. Hence, the results suggest that cholinergic neurons innervate the circular smooth muscle, and that opiate receptor agonists suppress transmission in these neurons. Neuronal SP in the esophagus may serve to enhance the contractile responses of esophageal smooth muscle.     

Activity of substance P on human skin and nasal airways

Nasal challenge and intradermal injection with substance P (SP) were performed in five normal subjects and in five patients suffering from allergic rhinitis. No clinical symptoms, local histamine release, or modifications of nasal airway resistance were observed when SP was insufflated in the nose. Conversely, intradermal injection with SP caused a wheal and flare reaction in all the studied subjects. The different response to SP is likely to be due to the heterogeneity of human skin and nasal mucosa mast cells as far as sensitivity to histamine-releasing agents is concerned. Our findings indicate that SP has no relevant effect on human nasal mucosa, even if a synergetic action of SP with other allergic mediators cannot be excluded. The role of SP in the pathogenesis of allergic diseases in humans remains to be defined and deserves further study.     

Demonstration of substance P immunoreactivity in the nucleus dorsalis of human spinal cord

Substance P immunoreactivity has been detected in varicosities around cell bodies of the nucleus dorsalis (Clarke's column) of the human spinal cord. This immunostaining probably represents neuropeptide immunoreactivity either in the nerve terminals of spinal interneurone, descending projections or in the primary dorsal root afferents which have been shown previously to synapse with the neurones of Clarke's column. The presence of substance P immunoreactivity in the human nucleus dorsalis suggests a role of substance P in the transmission of proprioceptive and exteroceptive information from the lower trunk and limbs to the cerebellum.     

Histamine involvement in the local and systemic microvascular effects produced by intradermal substance P

The cutaneous microvascular changes produced by intradermal substance P were quantitatively evaluated in both substance P-injected and contralateral, saline-injected guinea pig ears. Substance P evoked a dose-dependent increase in cutaneous microvascular permeability in both treated and untreated ears which was reduced, but not abolished, by a mepyramine-cimetidine combination. This indicates that the local effect of substance P on microvascular permeability and the effect on the contralateral ear (presumably the result of systemic substance P absorption) are both partially mediated by histamine. A cutaneous vasodilator response was also observed in substance P treated and contralateral ears, but a bell-shaped dose-response relationship was apparent. Unlike microvascular permeability, pretreatment with mepyramine and cimetidine failed to consistently attenuate the vasodilator response to substance P. Thus, a direct cutaneous vasodilator effect appars to predominate in both substance P-injected and saline-injected ears.     

The role of dopaminergic system in the immunostimulatory effects of substance P and its analog

Systemic administration of synthetic substance P or its analog EC-1 to CBA mice results in considerable stimulation of immune reactions. No stimulation is observed after disconnection of the hypothalamus from the pituitary. It is concluded that the immunostimulating effect of these peptides is mediated by the dopaminergic system, since it is abolished by the D₂ receptor blocker haloperidol. Translated fromByulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 123, No. 2, pp. 135–137, February, 1997     

Immunohistochemical localization of substance P in anencephalic human fetus spinal cord

The distribution of substance P (SP) in human anencephalic fetus spinal cord has been studied with the indirect immunofluorescence technique. The SP-like immunoreactivity was detected within plexuses of fibres localized in the superficial layers of the dorsal grey including the marginal zone and substantia gelatinosa, and also the dorsal funicular grey. The other spinal cord areas were devoid of SP-like immunoreactivity. Comparison with normal fetus spinal cord reveals that in both normal and anencephalic fetuses the dorsal SP-patterns are comparable. This study indicates that in human fetus spinal cord most of the SP-fibres dorsally localized, occur even if the brain itself does not develop.     

The substance P receptor on rat mast cells and in human skin

(D-Pro⁴ D-Trp^7,9,10)SP_4–11 (SPA) has been shown to be a competitive antagonist of the histamine releasing action of substance P in rat peritoneal mast cells. Antagonist activity of SPA is expressed in the concentration range 1 to 10 M, but at higher concentrations SPA releases histamine.SPA inhibits the flare response induced by substance P in human skin but is without effect on the wheal response. Up to 12.5 pmol SPA produces neither wheal nor flare response by itself.The structurally related peptide, kassinin, does not cause histamine release from rat mast cells at concentrations up to 10 M whereas the methyl ester of substance P was found to 1.6 times more active than substance P in this respect.The findings are discussed in terms of the classification of substance P receptors and the mechanism of wheal and flare in human skin.     

Localization of substance P and enkephalin by immunohistochemistry in the spinal cord of human fetus

The peroxidase-antiperoxidase method was used to study the distribution of substance P and enkephalin during development of the spinal cords of human fetuses. Thirty-seven cases were collected, ranging from 5- to 40-weeks-old (fetal ages). Both types of transmitters were present initially around the fifth week in the mantle layer of the base of the dorsal horn, around the tenth week at the anterior gray and the intermediate gray and around the sixth week at the marginal layer at the base of the ventrolateral funiculus. Substance P- and enkephalin-positive sites at the marginal layers at the base of the dorsolateral funiculus were evident in the same area at 5-6 weeks. The positive fibers in the dorsal horn were initially located in the superficial layers. By the eleventh week, the positive sites spread to other surface layers at the lateral sides of the dorsal horns bilaterally at all spinal levels above the sacral. In the sacral levels adjacent to the conus medullaris, the spreading to surface layers was not apparent bilaterally until the seventeenth week. By weeks 18-26 the positive sites penetrated deeper in the dorsal horn and by week 27 assumed the adult path. The enkephalin cell bodies were present in the Rexed layers I and II of the dorsal horn and the substance P-positive sites were apparent in the dorsal ganglia of the 28-40-week-old fetuses.