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)

We have previously shown the depletion of cutaneous calcitonin gene-related peptide (CGRP)- and substance P-containing nerves in human leprosy. The aims of this study were to investigate the temporal effects of leprosy on nerves in skin and spinal cord. Tissues were taken from nude mice, 6 and 12 months after inoculation of Mycobacterium leprae into the hind footpads, and from age-matched controls. Sections were immunostained with antisera to substance P or CGRP. After 6 months of infection, substance P- and CGRP-immunoreactive nerves were reduced in skin from all body areas; by 12 months, the reduction was substantially greater. In the spinal cord, sensory fibres immunoreactive for substance P had decreased compared with controls at 6 and 12 months [by 60 per cent (0.022 mm2) and 80 per cent (0.048 mm2), respectively, P less than 0.001], as with CGRP [30 per cent (0.018 mm2) (P less than 0.02) and 40 per cent (0.028 mm2) (P less than 0.01), respectively]. CGRP immunoreactivity was completely absent in motor neurones after 12 months of infection. Loss of CGRP- and substance P-immunoreactive fibres in skin and spinal cord, and CGRP in motor neurones is in accord with impaired pain sensation and muscle weakness in leprosy.
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PMID:Time-related decrease of substance P and CGRP in central and peripheral projections of sensory neurones in Mycobacterium leprae infected nude mice: a model for lepromatous leprosy in man. 169 40

Capsaicin (20-80 mg/kg, s.c.) reduced the inflammatory response to inoculation with Mycobacterium butyricum in the rat. The effect was apparent within 24 h, was partial, persisted for well over 20 days, and occurred irrespective of whether capsaicin was administered before or after the onset of inflammation, or at the time when the pathology reached peak. Capsaicin also attenuated the increase in substance P content in sciatic nerve, saphenous nerve, dorsal root ganglia, dorsal roots, and dorsal spinal cord (L4, L5) which occurs in rats with adjuvant arthritis. The data are consistent with a possible role of substance P in the peripheral manifestations of adjuvant arthritis.
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PMID:Effects of capsaicin on inflammation and on the substance P content of nervous tissues in rats with adjuvant arthritis. 618 16

We have investigated the effects of a chronic inflammatory stress on substance P (SP) levels in the hypothalami of rats given adjuvant-induced arthritis (AA). Fourteen days after injection of Mycobacterium butyricum, substance P concentrations in the paraventricular nucleus (PVN) and median eminence/arcuate nucleus were significantly increased. In AA rats injected intraperitoneally with the specific neurokinin-1 receptor antagonist RP67580, plasma ACTH and corticosterone concentrations were significantly elevated, and corticotropin-releasing hormone (CRH) mRNA in the PVN was increased compared to the AA group which received saline alone. The increases in hypothalamic SP in AA, together with the data demonstrating that HPA axis activity is enhanced in AA following injection of a SP antagonist, are consistent with the hypothesis that SP is acting as an inhibitor of CRH expression in this model of chronic inflammatory stress.
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PMID:Endogenous substance P inhibits the expression of corticotropin-releasing hormone during a chronic inflammatory stress. 747 53

1. Monoarthritis was induced in Lewis rats by interdermal injection in the left hind paw of a suspension of Mycobacterium tubercolusis in mineral oil (500 micrograms 100 microliters-1). Controls were injected with 100 microliters mineral oil. 2. Withdrawal latencies to thermal stimuli of the inflamed paw, the contralateral and both paws of control rats were measured at daily intervals after injection by the plantar test. 3. After detection of the pain threshold, rat spinal cords were removed and horizontal dorsal slices were mounted in a 3-compartment bath to measure electrically-evoked release of substance P-like immunoreactivity (SP-LI). 4. The inflamed paw of monoarthritic rats exhibited a lower pain threshold to thermal stimuli than the contralateral paw of the same animals and both paws of control rats. Inflamed paw hyperalgesia was maximal two days after injection, and declined gradually between 7 to 21 days with no evidence of excitability of withdrawal reflexes after 28 days. 5. During the 28 days study, monoarthritic rats gained less weight than control rats. 6. Electrical stimulation of the dorsal roots attached to rat isolated spinal cord slices induced a significant increase (174 +/- 18% of basal outflow which was 30.3 fmol 8 ml-1, n = 5) in SP-LI release. 7. One-week after induction of inflammation no differences in the amount of SP-LI released from the spinal cord of incomplete Freund's adjuvant-treated rats (IFA) and Freund's adjuvant-treated rats (CFA) were detected. Two weeks after, CFA spinal cord tended to release more SP-LI than IFA cords and, 21 days after injection, the spinal cord of CFA rats released significantly more peptide than IFA rats (17.8 +/- 2.8 fmol ml-1, n = 12 and 6.9 +/- 3.2 fmol ml-1, n = 9, respectively).8. Twenty-one days after treatment, the evoked release from monoarthritic rat spinal cords was increased by 263 + 42% (n = 3) in the presence of the GABAB receptor antagonist, CGP 36742 (100 micro M)which also significantly potentiated monoarthritis-induced hyperalgesia up to 45 min after injection(100 mgkg-1, i.p.).9. These findings may provide a basis for a novel approach to chronic pain therapy but also an explanation for the lack of analgesia produced by the GABAB agonist, baclofen, in chronic as compared to acute pain.
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PMID:Spinal cord SP release and hyperalgesia in monoarthritic rats: involvement of the GABAB receptor system. 753 91

1. The interaction between N-methyl-D-aspartate (NMDA) and NK1 tachykinin receptors was analyzed isobolographically in rats with inflammatory hyperalgesia induced by intraplantar injection of complete Freund's adjuvant-saline emulsion (CFA, 100 micrograms Mycobacterium tuberculosis). 2. Thermal hyperalgesia of the inflamed paw, determined by paw withdrawal response to a heat stimulus, was dose-dependently attenuated by intrathecal administration of an NMDA receptor antagonist, dextrorphan (2.5-40 micrograms, ED50 = 7.2 micrograms), and two NK1 tachykinin receptor antagonists, WIN 51,708 (0.01-200 micrograms, ED50 = 10.4 micrograms) or CP-96,345 (5-200 micrograms, ED50 = 82.1 micrograms). There was no effect of these agents on the nociceptive threshold of the non-inflamed paw. CP-96,344, an enantiomer of CP-96,345 that is inactive as an NK1 tachykinin receptor antagonist, slightly attenuated hyperalgesia at a dose of 200 micrograms. 3. Combinations of dextrorphan and WIN 51,708 were administered at fixed ratios (10%:90%; 41%:59%; 90%:10%). Isobolographic analysis revealed that the ED50s obtained from the three combination ratios were not significantly different from those that were expected from a simple additive effect. 4. Thus, an additive interaction was demonstrated between NMDA and NK1 tachykinin receptor systems at the spinal level. These results suggest that both NMDA and NK1 tachykinin receptors are activated in response to peripheral inflammation, but that they may contribute independently to development of hyperalgesia.
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PMID:An isobolographic analysis of the effects of N-methyl-D-aspartate and NK1 tachykinin receptor antagonists on inflammatory hyperalgesia in the rat. 882 63

Substance P (SP)-, neurokinin A (NKA)-, calcitonin gene-related peptide (CGRP)- and neuropeptide Y (NPY)-like immunoreactivities (-LI) were examined in cerebrospinal fluid (CSF), plasma and temporomandibular joint (TMJ) perfusates in rats 1 and 12 h after inoculation at the base of the tail (0.05 ml) or injection into the right TMJ (0.01 ml) of heat-killed Mycobacterium butyricum in paraffin oil. In the rats inoculated at the base of the tail (polyarthritic rats), there was a significant increase of CGRP-LI and NKA-LI. The changes in neuropeptide-LI were not as marked in the CSF of rats injected with adjuvant in one TMJ (monoarthritic rats) as in the polyarthritic group. Instead, the most significant changes in the monoarthritic rats were seen in the perfusates of both TMJs. The increases in SP-, NKA-, CGRP- and NPY-LI were significant for both TMJs and more pronounced than in the polyarthritic rats. The results show that inoculation of adjuvant at the base of the tail induces significant changes of neuropeptide-LI predominantly in CSF, whilst an intra-articular injection induces bilateral changes in neuropeptide-LI in joint perfusate. Therefore, two different neural mechanisms may be involved early in adjuvant-induced poly- and monoarthritis.
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PMID:Effects of adjuvant on neuropeptide-like immunoreactivity in experimentally induced temporomandibular arthritis in rats. 901 73

Temporomandibular joint (TMJ) arthritis was induced in female Lewis rats by unilateral injection of a suspension of heat-killed Mycobacterium butyricum in paraffin oil into the TMJ. Control rats received paraffin oil by the same route. Arthritic and control rats were pretreated either with capsaicin or denervation of the mandibular branch of the trigeminal nerve. Tissues were collected for neuropeptide extraction and analysed by radioimmunoassay and reverse-phase high-performance liquid chromatography. In all groups, the levels of substance P-(SP), calcitonin gene-related peptide- (CGRP) and neuropeptide Y- (NPY) like immunoreactivity (LI) were higher in the trigeminal ganglia than in the TMJs. In control rats, capsaicin significantly lowered the levels of SP-LI in the trigeminal ganglia and TMJ, but not CGRP-LI and NPY-LI. In the arthritic rats, capsaicin pretreatment significantly lowered the SP-LI and CGRP-LI in the trigeminal ganglia and TMJ, but not the NPY-LI. In the trigeminal ganglia the unilateral denervation significantly lowered SP-LI in control rats, and in arthritic rats SP-LI and CGRP-LI. On the denervated side of the arthritic TMJ, NPY-LI, SP-LI and CGRP- LI were significantly lowered as compared to the arthritic control rats and to the contralateral side. In this rat model, pretreatment with capsaicin and surgical denervation decreased the neuropeptide content in the trigeminal ganglia and the TMJ. The results clearly demonstrate a close interaction between increased neuropeptide release from sensory and sympathetic neurones after induction of arthritis in the rat.
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PMID:Effects of capsaicin in temporomandibular joint arthritis in rats. 946 May 41

To study the role of the nervous system in temporomandibular joint arthritis, substance P-, calcitonin gene-related peptide-, and neuropeptide Y-like immunoreactivity in the trigeminal ganglia and temporomandibular joint of rats was examined. Arthritis was induced in female Lewis rats through bilateral injection of a suspension of heat-killed Mycobacterium butyricum in paraffin oil into the temporomandibular joint. Control rats received paraffin oil via the same route. Tissues were collected for neuropeptide extraction 28 days after injection and analyzed by radioimmunoassay and reverse-phase high-performance liquid chromatography. Calcitonin gene-related peptide was significantly increased in the arthritic trigeminal ganglia. Substance P, calcitonin gene-related peptide, and neuropeptide Y in the arthritic temporomandibular joint were significantly increased as compared to controls. The results of this study show that sensory and sympathetic neuropeptides may possibly be associated with the development of arthritis in the temporomandibular joint of rats.
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PMID:Effects of adjuvant on neuropeptide-like immunoreactivity in the temporomandibular joint and trigeminal ganglia. 961 Mar 8

We sought to characterise the contribution of the neuropeptide substance P to the outcome of two models of footpad inflammation of differing severity. In an intense inflammatory model produced by intra-plantar Mycobacterium tuberculosus (10 mg/ml) substantial reductions in footpad swelling, histological outcome and mechanical hyperalgesia were observed from early time points in mice lacking the neurokin-1 receptor for substance P compared with wild-type controls. Conversely, in a less intense model (M. tuberculosus 1 mg/ml) no differences were observed other than for a reduction in mechanical hyperalgesia at later time points (day 9 onwards). The results point to a previously unrecognised influence of substance P on peripheral tissue injury and the maintenance of hyperalgesia during more severe or more chronic phases of inflammatory disease.
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PMID:Inhibition of inflammation and hyperalgesia in NK-1 receptor knock-out mice. 1462 45

Zinc metallopeptidases of bacterial pathogens are widely distributed virulence factors and represent promising pharmacological targets. In this work, we have characterized Zmp1, a zinc metallopeptidase identified as a virulence factor of Mycobacterium tuberculosis and belonging to the neprilysin (NEP; M13) family, whose X-ray structure has been recently solved. Interestingly, this enzyme shows an optimum activity toward a fluorogenic substrate at moderately acidic pH values (i.e., 6.3), which corresponds to those reported for the Mtb phagosome where this enzyme should exert its pathological activity. Substrate specificity of Zmp1 was investigated by screening a peptide library. Several sequences derived from biologically relevant proteins were identified as possible substrates, including the neuropeptides bradykinin, neurotensin, and neuropeptide FF. Further, subsequences of other small bioactive peptides were found among most frequently cleaved sites, e.g., apelin-13 and substance P. We determined the specific cleavage site within neuropeptides by mass spectrometry, observing that hydrophobic amino acids, mainly phenylalanine and isoleucine, are overrepresented at position P1'. In addition, the enzymatic mechanism of Zmp1 toward these neuropeptides has been characterized, displaying some differences with respect to the synthetic fluorogenic substrate and indicating that the enzyme adapts its enzymatic action to different substrates.
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PMID:Functional characterization of the Mycobacterium tuberculosis zinc metallopeptidase Zmp1 and identification of potential substrates. 2294 67


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