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)

The vanilloid receptor (VR1) protein functions both as a receptor for capsaicin and a transducer of noxious thermal stimuli. To determine the expression and targetting of this protein, we have generated antisera against both the amino and carboxy termini of VR1. Within the dorsal root and trigeminal ganglia of rats, VR1-immunoreactivity (VR1-ir) was restricted to small and medium sized neurons. VR1-ir was transported into both the central and peripheral processes of these primary afferent neurons, as evidenced by: (i) the presence of VR1-ir in nerve fibres and terminals in lamina I and lamina II of the superficial dorsal horn, and the association of VR1-ir with small diameter nerve fibres in the skin and cornea; (ii) the reduction of VR1-ir in the spinal cord after dorsal rhizotomy; and (iii) the accumulation of VR1-ir proximal to sciatic nerve ligation. At the ultrastructural level, VR1-ir was associated with plasma membranes of neuronal perikarya in dorsal root ganglia and nerve terminals in the dorsal horn. VR1-ir was also seen in nerve fibres and terminals in the spinal trigeminal nucleus and nucleus of the solitary tract. Within a large proportion of dorsal root ganglion neurons and the terminals of their axons, VR1-ir was colocalized with staining for the P2X3 purinoceptor, and with binding sites for the lectin IB4. Surprisingly, VR1-ir did not coexist substantially in nerve fibres and terminals that contain substance P and calcitonin gene-related peptide, suggesting complex mechanisms for the release of these neuropeptides in response to capsaicin application.
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PMID:Immunocytochemical localization of the vanilloid receptor 1 (VR1): relationship to neuropeptides, the P2X3 purinoceptor and IB4 binding sites. 1010 88

Many nociceptive dorsal root ganglion (DRG) sensory neurons express the high affinity nerve growth factor (NGF) receptor TRKA, and respond to NGF. However, many do not express TRKA but are thought to respond to glial cell-derived neurotrophic factor (GDNF) and related molecules. We therefore cultured DRG neurons in the presence of GDNF, and looked at the expression of substance P and of the capsaicin receptor, VR1, two nociceptive properties already known to be NGF regulated. Using several different approaches we demonstrated that GDNF produced clear increases in expression of both properties, comparable in magnitude to increases seen with NGF. Following axotomy, aberrant expression of substance P in A fibres may be involved in the generation of neuropathic pain. Factors regulating substance P and other properties in the absence of retrogradely transported NGF may therefore be of significance in neuropathic pain states.
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PMID:Glial cell line derived neurotrophic factor (GDNF) regulates VR1 and substance P in cultured sensory neurons. 1042 83

Evodiamine, a constituent of Evodiae Fructus (Evodia rutaecarpa Benth., Rutaceae), produced a bronchial contraction that is resistant to atropine and abolished by pretreatment with a mixture of the NK1 and NK2 receptor antagonists. Contractile responses to evodiamine were examined in guinea-pig isolated bronchus and compared with those to capsaicin. Both compounds evoked bronchial contraction in a concentration-dependent manner. Maximal contractions for evodiamine and capsaicin were observed at concentrations of 3 microM and 1 microM, respectively. Capsazepine (10 microM), an established antagonist of vanilloid receptor (capsaicin receptor), competitively inhibited the bronchial contraction evoked by evodiamine, suggesting that evodiamine activated vanilloid receptors. Evodiamine (3 microM) and capsaicin (1 microM) produced complete crossed tachyphylaxis. Both compounds desensitized tissues to subsequent additions of either evodiamine or capsaicin. These results suggest that the evodiamine-induced contractile response of the bronchus could be attributed to the resultant tachykinin release from sensory neurons by binding of evodiamine to vanilloid receptors. Rutaecarpine, which belongs to the same indoloquinazoline-type alkaloid as evodiamine, showed neither bronchoconstrictive, desensitizing effects nor vanilloid antagonistic effects at all the concentrations examined (up to 200 microM).
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PMID:The bronchoconstrictive action of evodiamine, an indoloquinazoline alkaloid isolated from the fruits of Evodia rutaecarpa, on guinea-pig isolated bronchus: possible involvement on vanilloid receptors. 1098 78

Capsaicin receptors are expressed in primary sensory neurons and excited by heat and protons. We examined the inflammation-induced changes of the level of VR1 capsaicin receptor mRNA in sensory neurons and the sensitivity of primary afferents to capsaicin. Carrageenan treatment induced axonal transport of VR1 mRNA, but not that of preprotachykinin mRNA, from the dorsal root ganglia to central and peripheral axon terminals. The sensitivity of central terminals to capsaicin, which was estimated by measuring the capsaicin-evoked release of glutamate from the dorsal horn, was increased by peripheral inflammation, and such an increase was suppressed by inhibiting the RNA translation in the dorsal horn with cycloheximide and an intrathecal injection of VR1 antisense oligonucleotides. Thus, peripheral inflammation induces the axonal transport of VR1 mRNA, which may be involved in the hypersensitivity of primary afferents to capsaicin and the production of inflammatory hyperalgesia.
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PMID:Axonal transport of VR1 capsaicin receptor mRNA in primary afferents and its participation in inflammation-induced increase in capsaicin sensitivity. 1125 80

Human immunodeficiency virus-1 (HIV-1) infection is associated with numerous effects on the nervous system, including pain and peripheral neuropathies. We now demonstrate that cultured rat dorsal root ganglion (DRG) neurons express a wide variety of chemokine receptors, including those that are thought to act as receptors for the HIV-1 coat protein glycoprotein120 (gp120). Chemokines that activate all of the known chemokine receptors increased [Ca(2+)](i) in subsets of cultured DRG cells. Many neurons responded to multiple chemokines and also to bradykinin, ATP, and capsaicin. Immunohistochemical studies demonstrated the expression of the CXCR4 and CCR4 chemokine receptors on populations of DRG neurons that also expressed substance P and the VR1 vanilloid receptor. RT-PCR analysis confirmed the expression of CXCR4, CX3CR1, CCR4, and CCR5 mRNAs in DRG neurons. Chemokines and gp120 produced excitatory effects on DRG neurons and also stimulated the release of substance P. Chemokines and gp120 also produced allodynia after injection into the rat paw. Thus these results provide evidence that chemokines and gp120 may produce painful effects via direct actions on chemokine receptors expressed by nociceptive neurons. Chemokine receptor antagonists may be important therapeutic interventions in the pain that is associated with HIV-1 infection and inflammation.
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PMID:Chemokines and glycoprotein120 produce pain hypersensitivity by directly exciting primary nociceptive neurons. 1143 78

Terminals in the rat spinal cord that express the vanilloid receptor VR1 are from small and medium dorsal root ganglion (DRG) neurons and appear prominent in lamina I and inner lamina II. Because primary afferents from these neurons can be myelinated or unmyelinated and their terminals in these laminae can be of various morphological and functional types, we undertook this study to identify the type(s) of VR1-positive afferent fibers and terminals. In the DRG, many small and medium-sized neurons are immunopositive. Under electron microscopy, dorsal root afferents that are immunopositive for VR1 are predominantly unmyelinated. Large numbers of VR1-positive terminals in lamina I are of the nonglomerular type and may contain dense core vesicles. VR1 immunoreactivity in terminals in lamina I is in good agreement with data on noxious, heat-sensitive neurons in the dorsal horn. Two types of glomerular afferent terminals in lamina II also are immunopositive for VR1. In both laminae, most VR1-positive terminals are distinct from substance P-positive terminals. However, the immunoreactivity in lamina II also is prominent in dendrites that are contacted by primary afferent endings. Because we also observed patchy immunostaining in cell bodies in lamina II, this unexpected result may reflect synthesis of VR1 by neurons in this lamina. However, because dorsal rhizotomy abolishes VR1 staining in both laminae I and II, it is suggested that the expression and intracellular dynamics of VR1 in lamina II neurons are controlled by presynaptic input.
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PMID:Vanilloid receptor VR1 is both presynaptic and postsynaptic in the superficial laminae of the rat dorsal horn. 1143 26

Meissner corpuscles (MCs) in the glabrous skin of monkey digits have at least three types of innervation as revealed by immunofluorescence. The previously well known Aalphabeta-fiber terminals are closely intertwined with endings from peptidergic C-fibers. These intertwined endings are segregated into zones that alternate with zones containing a third type of ending supplied by nonpeptidergic C-fibers. Although MCs are widely regarded as low-threshold mechanoreceptors, all three types of innervation express immunochemical properties associated with nociception. The peptidergic C-fiber endings have readily detectable levels of immunoreactivity (IR) for calcitonin gene-related peptide (CGRP) and substance P (SP). The Aalphabeta endings have relatively lower levels of IR for CGRP and SP as well as the SP neurokinin 1 receptor and vanilloid-like receptor 1. Both the Aalphabeta and peptidergic C-fiber endings were also labeled with antibodies for different combinations of adrenergic, opioid, and purinergic receptors. The nonpeptidergic C-fiber endings express IR for vanilloid receptor 1, which has also been implicated in nociception. Thus, MCs are multiafferented receptor organs that may have nociceptive capabilities in addition to being low-threshold mechanoreceptors.
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PMID:The Meissner corpuscle revised: a multiafferented mechanoreceptor with nociceptor immunochemical properties. 1154 34

The cloned vanilloid receptor VR1 can be activated by capsaicin and by thermal stimuli. The pattern of nerve terminals that contain VR1 in adult rat spinal cord does not correspond to axons that arise from a single subset of dorsal root ganglion neurons. Thus, we postulated that the basis underlying this complexity might be better understood from a developmental perspective. First, using capsaicin-induced hyperalgesia as a measure of VR1 function, we found that vanilloid receptors were functional as early as postnatal day 10 (P10), although hyperalgesia was of longer duration in adult. Interestingly, the appearance of VR1 protein in terminals of dorsal root ganglion neurons shifts over this postnatal period. From embryonic day 16 to P20, the majority of VR1 protein in the spinal cord was observed in lamina I. As animals matured, VR1 protein became more abundant in lamina II, particularly in the inner portion. Consistent with these observations, the number of dorsal root ganglion neurons coexpressing VR1 and isolectin B4 binding sites doubled while the number of neurons that had both VR1 and substance P remained relatively constant from P2 to P10. In peripheral processes, the number of VR1-positive nerve fibres and terminals in cutaneous structures in postnatal day 10 was half of that in adults. We also show that the association of VR1 with Ret is the reciprocal of the association of VR1 with Trk A. These results suggest that neurotrophins may regulate the extent to which populations of dorsal root ganglion neurons express VR1.
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PMID:Developmental shift of vanilloid receptor 1 (VR1) terminals into deeper regions of the superficial dorsal horn: correlation with a shift from TrkA to Ret expression by dorsal root ganglion neurons. 1155 80

Peripheral cranial sensory nerves projecting into the oral cavity receive food intake stimuli and transmit sensory signals to the central nervous system. To describe and compare the features of the cranial sensory ganglia that innervate the oral cavity, i.e., the trigeminal, petrosal, and geniculate ganglia (TG, PG, and GG, respectively), in situ hybridization was conducted using riboprobes for neurotrophin receptors (TrkA, TrkB, and TrkC), a neurotransmitter (substance P), and ion channels important for thermosensation (VR1 and TREK-1). In TG, all in six probes yielded positive signals to various extent in intensity and frequency. In addition, a strong correlation between the expression of VR1 and those of TrkA and substance P was observed as in the case of the dorsal root ganglia. In PG, positive signals to all six probes were also detected, and the correlation of expression was similar to that shown by TG. On the other hand, most cells in GG were positive to the TrkB probe, and a small number of cells were positive to the TrkC probe, but no significant signal was observed for the other four probes. These results indicate that TG and PG consist of cells that are heterogeneous in terms of neurotrophin requirement and somatosensory functions, and that GG seems to consist mainly of a homogeneous cell type, gustatory neurons. In conclusion, TG, PG, and GG, show gene expression characteristics intrinsic to the three ganglia. It is also concluded that TG and a portion of PG project several types of somatosensory nerves. This is consistent with the finding that GG and a portion of PG project gustatory nerves.
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PMID:A comparative study of three cranial sensory ganglia projecting into the oral cavity: in situ hybridization analyses of neurotrophin receptors and thermosensitive cation channels. 1158 88

Interstitial cells of Cajal (ICC) are important regulatory cells in the smooth muscle coats of the digestive tract. Expression of the Kit receptor tyrosine kinase was used in this study as a marker to study their distribution and development in the striated musculature of the mouse esophagus. Sections and whole-mounts were studied by immunohistochemistry. KitW-lacZ transgenic mice, which carry the lacZ reporter gene inserted in place of the first exon of the Kit gene, were processed for Xgal histochemistry, for quantitative analysis and for ultrastructural studies. Spindle-shaped ICC were scarce in both muscle layers of the thoracic esophagus, while their number increased steeply toward the cardia in the striated portion of the intraabdominal esophagus. They did not form networks and had no relationship with intrinsic myenteric ganglia and motor end-plates. They were often close to nerve fibers immunoreactive for neuronal nitric oxide synthase (nNOS), vasoactive intestinal polypeptide (VIP) or neuropeptide Y (NPY), but not to fibers immunoreactive for substance P (SP), calcitonin gene related peptide (CGRP), enkephalin, or the capsaicin receptor VRI. They were present in the fetus but absent in adult ICC-deficient KitW-lacZ/KitWv mice. Interstitial cells of Cajal were identified by electron microscopy by their ultrastructure in the striated muscle of the esophagus and exhibited Xgal labeling, while fibroblasts and muscle cells were unlabeled. Interstitial cells of Cajal are scattered between striated muscle cells in the mouse esophagus. They are close to nerves with defined neurochemical coding and could possibly represent specialized esophageal spindle proprioceptors.
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PMID:Interstitial cells of Cajal in the striated musculature of the mouse esophagus. 1168 70


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