Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P20366 (substance P)
 21,176 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Substance P (SP) and other related tachykinins such as neurokinin B (NKB) have been studied widely as mediators of sensory information. The release of SP into the dorsal horn of the spinal cord is increased during nociception, and SP activates nociception-specific dorsal horn neurons. The tachykinin NKB has antinociceptive effects in the spinal cord and is contained in intrinsic spinal neurons; thus, NKB may also contribute to the processing of sensory information. Both neurokinin-1 (NK-1) and neurokinin-3 (NK-3) receptors have been localized in the superficial laminae of the dorsal horn. This study investigated changes in NK-1 and NK-3 receptor mRNA expression during nociception. Following injection of either formalin or complete Freund's adjuvant (CFA) into one hindpaw, the levels of expression of NK-1 and NK-3 mRNAs in the spinal cord dorsal horn and preprotachykinin (PPT) mRNA expression in the lumbar dorsal root ganglia (DRG) were quantitated using solution hybridization-nuclease protection assays. Peptide and receptor mRNA expression levels were normalized to beta-actin mRNA levels, which did not change during the treatments. Formalin (2 or 6 hr) or CFA (4 d) injection produced approximately a twofold increase in SP-encoding PPT mRNA expression in the ipsilateral lumbar DRG. Increased activity in primary afferent neurons containing SP may stimulate the production of SP precursors, providing substrate for increased SP production, release, and turnover in the dorsal horn and periphery.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:NK-1 and NK-3 type tachykinin receptor mRNA expression in the rat spinal cord dorsal horn is increased during adjuvant or formalin-induced nociception. 830 59

Angiotensin converting enzyme (ACE) -inhibitors inhibit degradation of inflammatory mediators substance P (SP) and bradykinin, which may further stimulate the synthesis of prostaglandins. The resulting increase in inflammatory mediators in tissues is suggested to be the reason for the dry cough, involving sensory C-fiber activation, among patients receiving ACE-inhibitor therapy. In the present study, the effect of an ACE-inhibitor, captopril, on ocular irritative responses was studied in the rabbit. Intravenous captopril decreased markedly the blood pressure and the intraocular pressure (IOP) modestly. Topical neutral formaldehyde elicits an irritative response in the eye mediated through sensory neuropeptides SP and calcitonin gene-related peptide (CGRP). Following topical neutral formaldehyde, the increase in IOP and breakdown of the blood-aqueous barrier were inhibited by captopril, while miosis was not affected. Cyclic AMP (cAMP) content in the aqueous humour was increased by captopril, and this increase was inhibited by indomethacin. Following YAG-laser anterior capsulotomy, captopril inhibited the increase in IOP, breakdown of the blood-aqueous barrier and miosis. The present study demonstrates that use of short-term administration of captopril prior to sensory nerve stimulation or YAG laser anterior capsulotomy does not enhance the ocular responses to these stimuli in the rabbit. In the present study, captopril inhibited these responses, at least partly by decreasing the blood pressure.
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PMID:Effect of captopril on ocular irritative response to topical neutral formaldehyde and YAG-laser capsulotomy in the rabbit. 859 Feb 56

Pituitary adenylate cyclase-activating peptide (PACAP)-like immunoreactivity was demonstrated by immunocytochemistry together with calcitonin gene-related peptide (CGRP)-like immunoreactivity in small to medium-sized neurons in the trigeminal ganglion and in nerve fibers in the iris, ciliary body, cornea, choroid and sclera of the rabbit eye. The regional distribution of PACAP-27- and PACAP-38-like immunoreactivity in the eye was studied by radioimmunoassay: the highest concentrations were found in the iris sphincter and ciliary body. The distribution pattern resembled that of CGRP-like immunoreactivity, which is a well-known constituent of sensory C-fibre neurons. Intravitreal injection of PACAP-27 or PACAP-38 induced conjunctival hyperemia, swelling of the anterior segment of the eye, miosis and breakdown of the blood-aqueous barrier, manifested as a marked aqueous flare response. Tetrodotoxin pretreatment inhibited the conjunctival hyperemia, the swelling of the anterior segment of the eye, and the miosis but not the aqueous flare response. The concentration of PACAP-like immunoreactivity in the aqueous humor was increased greatly following infrared irradiation of the iris, topical application of formaldehyde to the cornea, or intravitreal injection of endotoxin or bovine serum albumin. Also the concentration of CGRP-like immunoreactivity in the aqueous humor was increased greatly. Both in vivo and in vitro studies showed that capsaicin caused a parallel release of PACAP-like immunoreactivity and CGRP-like immunoreactivity from the uvea. Injection of PACAP-27 and PACAP-38 resulted in the release of CGRP-like immunoreactivity (and PACAP-like immunoreactivity) into the aqueous humor and PACAP-27 and PACAP-38 were also found to evoke tachykinin-mediated contractions of the isolated iris sphincter muscle, indicating that PACAP induces positive feedback on C-fibres. Thus, PACAP is a sensory neuropeptide in the eye. Since the PACAP-induced ocular responses mimicked the symptoms of inflammation, and since the PACAP-like immunoreactivity concentration in the aqueous humor was greatly increased following noxious stimulation, we suggest that it takes part in the inflammatory responses of the rabbit eye.
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PMID:Distribution and effects of pituitary adenylate cyclase-activating peptide in the rabbit eye. 863 27

We have investigated the effects of CP-99,994 [(+)-(2s,3s)-3-(2-methoxybenzylamino)-2-phenylpiperidine], a tachykinin NK1 receptor antagonist, HOE 140 (D-Arg[Hyp3,Thi5,D-Tic7,Oic8]bradykinin), a bradykinin B2 receptor antagonist, and ketotifen (4-(1-methyl-4-piperidylidene)4 H-benzo[4,5]cycloheptal[1,2-b]thiophen-10(9H)-one hydrogen fumarate), a histamine H1 receptor antagonist with mast cell-stabilizing properties, on microvascular leakage induced by gaseous formaldehyde. Extravasation of Evans blue dye into airway tissues was used as an index of airway microvascular leakage. Leakage of dye in the trachea and main bronchi increased significantly in a concentration-dependent fashion after 10 min inhalation of formaldehyde (5-45 parts per million (ppm)). The airway response induced by 10 min inhalation of 15 ppm formaldehyde (trachea: 119.5 +/- 13.9 ng/mg, n = 7; main bronchi: 139.6 +/- 7.9 ng/mg, n = 7) was abolished by the administration of CP-99,994 (3 and 6 mg/kg i.v.), but not by the administration of HOE 140 (0.65 mg/kg i.v.) nor ketotifen (1 mg/kg i.v.). The increase in vascular permeability induced by formaldehyde in the rat airway was mediated predominantly by NK1 receptor stimulation. Activation of bradykinin receptors and mast cells did not appear to play an important role in this airway response.
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PMID:Role of tachykinin and bradykinin receptors and mast cells in gaseous formaldehyde-induced airway microvascular leakage in rats. 883 17

The presence of neuropeptide-containing sensory, parasympathetic and sympathetic nerves in human nasal mucosa is well established. However, information regarding the neuropeptide distribution in nasal polyps is still lacking. The aim of this study was to compare immunohistologically the presence and distribution of substance P (SP), vasoactive intestinal peptide (VIP) and bombesin-flanking peptide (BFP) in normal nasal mucosa and nasal polyps. The expression was studied using Formalin-fixed and paraffin-embedded biopsy sections from 20 patients with nasal polyps and 10 controls with normal nasal mucosa from the anterior part of the inferior turbinate. Indirect immunohistochemistry (APAAP method) with mono- and polyclonal antibodies was used. None of the control group but 5 patients of the nasal polyp group had an atopic disease. Comparing localization and intensity of the immunohistological reaction in nasal mucosa and nasal polyp tissue, there was no difference in the expression of the three neuroendocrine substances. There was no difference of expression in the polyposis group itself concerning allergic and nonallergic subjects. The results indicate that VIP, SP and BFP have an equal distribution in nasal polyps and normal nasal mucosa.
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PMID:Expression of vasoactive intestinal peptide, substance P and bombesin-flanking peptide in nasal polyps. 888 11

The neurokinins, substance P (SP) and neurokinin A (NKA) represent natural, nonspecific ligands of NK1 and NK2 receptors. In our study in conscious rats, we tested the hypothesis that neurokinins, especially SP, are used by neuronal circuits to generate cardiovascular and behavioral responses to stress by using the selective, high-affinity, nonpeptide antagonists of NK1 and NK2 receptors, CP-96, 345, RP 67580 and SR 48968, respectively, Formalin injected s.c. through a chronically implanted catheter in the region of the lower leg was used as a stress stimulus. The antagonists and their inactive enantiomers, RP 68651 and SR 48965, as a control for nonspecific activity, were injected intracerebroventricularly (i.c.v.) 10 min before the s.c. injection of formalin. Formalin (2.5%, 50 microliters, s.c.) induced a marked increase in mean arterial pressure (MAP) and heart rate (HR) as well as hind limb grooming/biting (HG) as the dominant behavioral manifestation. Pretreatment with the NK1 receptor antagonist, CP-96,345 (5 nmol, i.c.v.), significantly attenuated only the HR (-54%; P < .01) but not the MAP response to formalin. The NK1 receptor antagonist, RP 67580, injected i.c.v. at doses of 100, 500 and 2500 pmol significantly reduced both, the MAP and HR responses to formalin by maximally 63% (P < .01) and 52% (P < .01), respectively. In a separate set of experiments, we compared the effect of the individual and simultaneous blockade of central NK1 and NK2 receptors on the cardiovascular and behavioral responses to formalin stress. Pretreatment with RP 67580 (100 pmol, i.c.v.) attenuated the MAP (-30%; P < .05), HR (-40%; P < .01) and HG (P < .05) responses to formalin. The NK2 receptor antagonist, SR 48968 (650 pmol, i.c.v.), affected neither the cardiovascular nor the behavioral responses. i.c.v. pretreatment with both tachykinin receptor antagonists (RP 67580: 100 pmol; SR 48968: 650 pmol) reduced the MAP, HR and HG responses to formalin to the same extent as RP 67580 alone. Pretreatment with the inactive enantiomers, RP 68651 (100 pmol, i.c.v.) and SR 48965 (650 pmol, i.c.v.) did not alter the cardiovascular and behavioral responses to formalin. Our results demonstrate that centrally administered NK1 receptor antagonists inhibit the cardiovascular and behavioral reactions in response to a noxious stimulus. They provide first pharmacological evidence that endogenous SP acts as mediator of stress responses in the brain.
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PMID:Effect of tachykinin receptor inhibition in the brain on cardiovascular and behavioral responses to stress. 899 2

The involvement of bradykinin and some other inflammatory mediators in formalin-induced oedema and plasma extravasation was examined. Formalin was injected in rat paws at two doses, 1.75% or 5%. The lower dose induced the development of an immediate oedema associated with a progressive accumulation of 125I-labelled albumin in the paws. These changes were suppressed by pretreatment with capsaicin or xylocaine. They were abolished by RP67580, a NK1 receptor antagonist, and increased by phosphoramidon or diprotin A. They were not affected by HOE140, a bradykinin B2 antagonist, captopril, methysergide, mepyramine, indomethacin, ketoprofen or L-N(G)-nitroarginine. The higher dose of formalin induced a swelling of the paws which took place in two phases associated with two periods of increase in vascular permeability. This oedema was reduced by pretreatment with capsaicin but not with xylocaine. It was reduced by RP67580 injected before or 30 min after formalin. It was inhibited by mepyramine, methysergide, indomethacin and NS-398, a cyclooxygenase-2 inhibitor. It was not modified by HOE140. Its development was similar in normal and kininogen-deficient rats. We concluded that formalin administered at a low dose induces an oedema which mainly results from a neurogenic inflammation mediated by neuropeptides such as substance P. At higher doses, formalin induces an oedema which mainly depends on the release of substance P, prostanoids, 5-hydroxytryptamine and histamine. Bradykinin plays no significant role in the vascular changes whereas this peptide has been reported to participate in the stimulation of nociceptive afferent neurons. This discrepancy could be explained by a difference in the threshold of stimulation of the nociceptive neurons and that of the cells of the vascular walls, or by a formation of kinins in close contact of the neurons.
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PMID:The inflammatory reaction induced by formalin in the rat paw. 1020 9

Recent pharmacological evidence has implicated substance P and neurokinin A, natural ligands for neurokinin-1 and neurokinin-2 receptors, respectively, as neurotransmitters in brain neuronal circuits activated upon noxious stimulation. The expression of the inducible transcription factor, c-Fos, was used to identify areas in the brain activated by a noxious stimulus (the subcutaneous injection of formalin), and to investigate the effects of intracerebroventricular administration of selective, nonpeptide antagonists for neurokinin-1 and neurokinin-2 tachykinin receptors on the neural activity in these areas and on the behavioural response to formalin-induced pain. Formalin (5%, 50 microl), injected subcutaneously through a chronically implanted catheter in the region of the lower hindlimb, increased c-Fos expression in a number of brain areas related to nociceptive transmission or the integration of stress responses. Grooming behaviour, licking and biting directed to the injected site, was the most frequent behavioural response. Intracerebroventricular pretreatment of rats with either RP 67580 (500 pmol), the active enantiomer of a neurokinin-1 receptor antagonist, or with SR 48968 (500 pmol), the active enantiomer of a neurokinin-2 receptor antagonist, reduced the formalin-induced c-Fos staining in the prefrontal cortex, dorsomedial and ventromedial nuclei of the hypothalamus, the locus coeruleus and the periaqueductal gray. The neurokinin-1, but not the neurokinin-2, receptor antagonist attenuated the formalin-induced activation of c-Fos in the paraventricular nucleus of the hypothalamus. Simultaneous intracerebroventricular pretreatment with both neurokinin-1 and neurokinin-2 receptor antagonists did not produce any additional inhibitory effect on the post-formalin c-Fos expression. None of the tachykinin receptor antagonists had an effect on the formalin-induced c-Fos expression in the septohypothalamic nucleus, medial thalamus, parabrachial nucleus and central amygdaloid nucleus, indicating that neurotransmitters other than neurokinins are most probably responsible for the activation of these areas in response to noxious stimulation. While both tachykinin receptor antagonists reduced the grooming behaviour to formalin, the neurokinin-1 receptor antagonist was clearly more effective than the neurokinin-2 receptor antagonist. Intracerebroventricular pretreatment of rats with the inactive enantiomers of the tachykinin receptor antagonists, RP 68651 and SR 48965, was without effect. Our results show that (i) the modified formalin test elicited an intense grooming behaviour and expression of c-Fos in numerous forebrain and brainstem areas, (ii) both tachykinin receptor antagonists were able to attenuate the behavioural response to pain and to reduce the formalin-induced c-Fos expression in some, but not all, brain areas, and (iii) the neurokinin-1 antagonist, RP 67580, was more effective in inhibiting the behavioural response to formalin and the pain-induced activation of c-Fos than the antagonist for neurokinin-2 receptors, SR 48968, indicating that neurokinin-1 receptors are preferentially activated in neurokinin-containing pathways responding to noxious stimuli. Our results demonstrate that blockade of brain tachykinin receptors, especially of the neurokinin-1 receptor, reduces the behavioural response to pain and the pain-induced c-Fos activation in distinct brain areas which are intimately linked with nociceptive neurotransmission and the initiation and integration of central stress responses. Together with the previous findings of the inhibition of hypertensive and tachycardic responses to pain, the present data indicate that tachykinin receptor antagonists can effectively inhibit the generation of an integrated cardiovascular and behavioural response pattern to noxious stimuli.
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PMID:Tachykinin receptor inhibition and c-Fos expression in the rat brain following formalin-induced pain. 1067 Apr 49

Pharmacologic studies implicate the involvement of substance P in spinal nociceptive processing during the formalin test. However, no direct measurement of the temporal changes in substance P levels within the spinal cord of conscious animals has been reported. Further, dissociation between substance P levels and formalin-evoked nocifensive behavior may exist in diabetic rats, as exaggerated hyperalgesic behavior coexists with reduced peripheral nerve substance P levels. The present study was performed to directly measure the appearance of substance-P-like immunoreactivity (SP-LI) in spinal CSF of conscious, unrestrained rats using microdialysis techniques following injection of formalin into the hindpaw. The effect of diabetes upon formalin-evoked SP-LI levels in spinal CSF dialysates was also determined. In control rats, SP-LI increased in spinal dialysates following formalin injection and levels were maximal 20-30 min after injection, rising to 325% of basal values (p<0.02). Diabetic rats exhibited reduced (p<0.05) SP-LI in their spinal roots, while basal levels in spinal CSF were not different from controls. Formalin-evoked nocifensive behavior was increased in diabetic rats but SP-LI levels in spinal CSF dialysates after paw formalin injection were significantly (p<0.05) attenuated, reaching a maximum of only 161% of basal levels. This was accompanied by attenuated swelling at the formalin injection site and increased thermal response latencies. While increased SP-LI in spinal CSF coincides with phase 2 behavior in the formalin test and may contribute to spinal nociceptive processing during this period, exaggerated spinal substance P release is unlikely to underlie the increased nocifensive behavior seen in diabetic rats.
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PMID:Elevated substance-P-like immunoreactivity levels in spinal dialysates during the formalin test in normal and diabetic rats. 1067 7

In the present work, the effects of tachykinin receptor antagonists on formalin-induced c-fos expression in the rat spinal cord were studied by a combination of immunocytochemical and neuropharmacological methods. Formalin injected into a hindpaw of rat only resulted in c-fos expression in the ipsilateral dorsal horn neurons of the spinal cord. Fos-positive neurons were distributed mainly in medial parts of the lamina I and the outer lamina II. A moderate number of Fos-positive neurons were present in laminae IV-V, and a few in the inner lamina II and in laminae III, VI and X. Selective NK-1 antagonist L-668, 169 (0.1, 1 and 10 micrograms) administered intrathecally before injection of formalin into a hindpaw significantly reduced the number of Fos-labeled neurons in the dorsal horn in a dose-dependent manner (P < 0.01), while selective NK-2 antagonist L-659, 877 (10 micrograms) and selective NK-3 antagonist SR-142, 801 (10 micrograms) were ineffective (P > 0.05). Our results indicated that NK-1 receptor mediated formalin-induced c-fos expression in the spinal cord, suggesting NK-1 receptor might play an important role in the spinal transmission of nociceptive messages.
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PMID:[Neurokinin-1 receptor mediated formalin-induced c-fos expression in the rat spinal cord]. 1132 43


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