Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

TRPA1 is a member of the transient receptor potential (TRP) channel family present in sensory neurons. Here we show that vanilloid receptor (TRPV1) stimulation with capsaicin and activation of TRPA1 with allyl isothiocyanate or cinnamaldehyde cause a graded contraction of the rat urinary bladder in vitro. Repeated applications of maximal concentrations of the agonists produce desensitization to their contractile effects. Moreover, contraction caused by TRPA1 agonists generates cross-desensitization with capsaicin. The TRP receptor antagonist ruthenium red (10-100 microM) inhibits capsaicin (0.03 microM), allyl isothiocyanate (100 microM) and cinnamaldehyde (300 microM)-induced contractions in the rat urinary bladder. The selective TRPV1 receptor antagonist SB 366791 (10 microM) blocks capsaicin-induced contraction, but partially reduces allyl isothiocyanate- or cinnamaldehyde-mediated contraction. However, allyl isothiocyanate and cinnamaldehyde (10-1000 microM) completely fail to interfere with the specific binding sites for the TRPV1 agonist [(3)H]-resiniferatoxin. Allyl isothiocyanate or cinnamaldehyde-mediated contractions of rat urinary bladder, which rely on external Ca(2+) influx, are significantly inhibited by tachykinin receptor antagonists as well as by tetrodotoxin (1 microM) or indomethacin (1 microM). Allyl isothiocyanate-induced contraction is not changed by atropine (1 microM) or suramin (300 microM). The exposure of urinary bladders to allyl isothiocyanate (100 microM) causes an increase in the prostaglandin E(2) and substance P levels. Taken together, these results indicate that TRPA1 agonists contract rat urinary bladder through sensory fibre stimulation, depending on extracellular Ca(2+) influx and release of tachykinins and cyclooxygenase metabolites, probably prostaglandin E(2). Thus, TRPA1 appears to exert an important role in urinary bladder function.
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PMID:Contractile mechanisms coupled to TRPA1 receptor activation in rat urinary bladder. 1672 14

TRPA1 is an excitatory ion channel expressed by a subpopulation of primary afferent somatosensory neurons that contain substance P and calcitonin gene-related peptide. Environmental irritants such as mustard oil, allicin, and acrolein activate TRPA1, causing acute pain, neuropeptide release, and neurogenic inflammation. Genetic studies indicate that TRPA1 is also activated downstream of one or more proalgesic agents that stimulate phospholipase C signaling pathways, thereby implicating this channel in peripheral mechanisms controlling pain hypersensitivity. However, it is not known whether tissue injury also produces endogenous proalgesic factors that activate TRPA1 directly to augment inflammatory pain. Here, we report that recombinant or native TRPA1 channels are activated by 4-hydroxy-2-nonenal (HNE), an endogenous alpha,beta-unsaturated aldehyde that is produced when reactive oxygen species peroxidate membrane phospholipids in response to tissue injury, inflammation, and oxidative stress. HNE provokes release of substance P and calcitonin gene-related peptide from central (spinal cord) and peripheral (esophagus) nerve endings, resulting in neurogenic plasma protein extravasation in peripheral tissues. Moreover, injection of HNE into the rodent hind paw elicits pain-related behaviors that are inhibited by TRPA1 antagonists and absent in animals lacking functional TRPA1 channels. These findings demonstrate that HNE activates TRPA1 on nociceptive neurons to promote acute pain, neuropeptide release, and neurogenic inflammation. Our results also provide a mechanism-based rationale for developing novel analgesic or anti-inflammatory agents that target HNE production or TRPA1 activation.
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PMID:4-Hydroxynonenal, an endogenous aldehyde, causes pain and neurogenic inflammation through activation of the irritant receptor TRPA1. 1768 94

Transient receptor potential (TRP) A1 channels are cation channels found preferentially on nociceptive sensory neurones, including capsaicin-sensitive TRPV1-expressing vagal bronchopulmonary C-fibres, and are activated by electrophilic compounds such as mustard oil and cinnamaldehyde. Oxidative stress, a pathological feature of many respiratory diseases, causes the endogenous formation of a number of reactive electrophilic alkenals via lipid peroxidation. One such alkenal, 4-hydroxynonenal (4HNE), activates TRPA1 in cultured sensory neurones. However, our data demonstrate that 100 microm 4HNE was unable to evoke significant action potential discharge or tachykinin release from bronchopulmonary C-fibre terminals. Instead, another endogenously produced alkenal, 4-oxononenal (4ONE, 10 microm), which is far more electrophilic than 4HNE, caused substantial action potential discharge and tachykinin release from bronchopulmonary C-fibre terminals. The activation of mouse bronchopulmonary C-fibre terminals by 4ONE (10-100 microm) was mediated entirely by TRPA1 channels, based on the absence of responses in C-fibre terminals from TRPA1 knockout mice. Interestingly, although the robust increases in calcium caused by 4ONE (0.1-10 microm) in dissociated vagal neurones were essentially abolished in TRPA1 knockout mice, at 100 microm 4ONE caused a large TRPV1-dependent response. Furthermore, 4ONE (100 microm) was shown to activate TRPV1 channel-expressing HEK cells. In conclusion, the data support the hypothesis that 4-ONE is a relevant endogenous activator of vagal C-fibres via an interaction with TRPA1, and at less relevant concentrations, it may activate nerves via TRPV1.
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PMID:Relative contributions of TRPA1 and TRPV1 channels in the activation of vagal bronchopulmonary C-fibres by the endogenous autacoid 4-oxononenal. 1862 2

Injury to the peripheral nerves often induces produces spontaneous pain, hyperalgesia (increased responsiveness to noxious stimuli), and allodynia (painful responses to normally innocuous stimuli). In contrast to inflammatory pain, the currently available therapeutics for neuropathic pain are either relatively ineffective or accompanied by considerable side effects. Numerous animal models of chronic pain following nerve injury have been introduced. All these neuropathic pain models are generated by partial nerve injury, where a few primary afferents are axotomized, while the others are spared. Among these models, the L5 spinal nerve ligation (SNL) model is unique because in this model, the L4 dorsal root ganglion (DRG) neurons are clearly separated from the axotomized L5 DRG neurons. Previous studies have focused considerable attention on the directly damaged primary afferents and their influence on the activity of the dorsal horn neurons. However, increasing evidence suggests that DRG neurons with intact axons also exhibit alterad excitability and gene expression, and these changes might play functional roles in the pathomechanisms of neuropathic pain. For example, L5 SNL increases the expression of substance P, calcitonin gene-related peptide, brain-derived neurotrophic factor, and the transient receptor potential ion channels TRPV1 and TRPA1 in the uninjured L4 DRG neurons. Furthermore, compelling evidence suggests that the glial cells in the spinal cord may also play a role in the pathogenesis of neuropathic pain. Recent studies have shown that peripheral nerve injury results in the activation of mitogen-activated protein kinases (MAPK) in spinal glial cells and that MAPK inhibitors diminish nerve injury-induced pain hypersensitivity. This review mainly focuses on the DRG neurons and spinal glial cells and will review the roles of MAPK in the nociceptive pathways for neuropathic pain.
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PMID:[Contribution of primary sensory neurons and spinal glial cells to pathomechanisms of neuropathic pain]. 1851 70

Stimulation of primary sensory neurons with capsaicin or mustard oil leads to phosphorylation of extracellular signal-regulated protein kinase 1/2 (p-ERK1/2) via activation of transient receptor potential V1 (TRPV1) or TRPA1, respectively. p-ERK1/2 was determined by Western immunoblotting in the dorsal root ganglia and in the sciatic nerve of rats following either systemic or perineural capsaicin treatment, or mustard oil application to the hind paw skin. To investigate the possible involvement of neurokinin 1 (NK(1)) and NK(2) receptors as well as of nitric oxide, the selective antagonists, SR140333 for NK(1) and SR48968 for NK(2), and the nitric oxide synthase inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME), were employed. The increase of p-ERK1/2 after systemic capsaicin treatment was markedly attenuated by SR140333, while only the increase in the dorsal root ganglia was impaired by SR48968; in contrast, inhibition of nitric oxide synthase had no effect. Perineural capsaicin induced an increase in p-ERK1/2 in the ipsilateral sciatic nerve and in the dorsal root ganglia. This effect was not influenced by SR140333 or L-NAME. We found for the first time that mustard oil application to the hind paw skin caused an increase in p-ERK1/2 in the sciatic nerve and in the dorsal root ganglia and only the phosphorylation in the latter was attenuated by SR140333 while L-NAME showed no effect. From the present results, it may be assumed that capsaicin- or mustard oil-induced p-ERK1/2 in sensory neurons is not solely directly linked to TRPV1 or TRPA1 channels, but under certain conditions NK(1)- and NK(2)-mediated mechanisms are involved.
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PMID:Capsaicin- and mustard oil-induced extracellular signal-regulated protein kinase phosphorylation in sensory neurons in vivo: effects of neurokinins 1 and 2 receptor antagonists and of a nitric oxide synthase inhibitor. 1915 48

Two tachykinin peptides, substance P (SP) and hemokinin-1 (HK-1), and three transient receptor potential (TRP) channels, TRPV1, TRPA1 and TRPM8, are similarly localized in the spinal dorsal horn and dorsal root ganglion, suggesting that TRP channels may be related or modulated by these tachykinin peptides. Thus, to clarify whether the responses of TRP channels are modulated by SP or HK-1, the effects of pretreatment with SP or HK-1 on the induction of scratching behavior by TRP channel agonists were examined. Pretreatment with SP or HK-1 enhanced the induction of scratching behavior by resiniferatoxin, a TRPV1 agonist, whereas scratching behavior induced by menthol, a TRPM8 agonist, was suppressed by pretreatment with these peptides. On the other hand, pretreatment with SP, but not HK-1, suppressed the induction of scratching behavior by cinnamaldehyde, a TRPA1 agonist. Taken together, the present results indicate that SP or HK-1 differentially modulated the response of TRPV1, TRPA1 or TRPM8 channel.
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PMID:Differential effects of substance P or hemokinin-1 on transient receptor potential channels, TRPV1, TRPA1 and TRPM8, in the rat. 1992 30

Afferent fibers innervating the gastrointestinal tract have major roles in consciously evoked sensations including pain. However, little is known about the molecules involved in mechanonociception from the upper gastrointestinal tract. We recently reported that activation of extracellular signal-regulated kinase 1/2 (ERK1/2), a member of the mitogen-activated protein kinase cascade in primary afferent neurons, was induced by noxious gastric distention in the rat, and that the activation of ERK1/2 in dorsal root ganglion (DRG) neurons can be implicated in acute visceral pain. Transient receptor potential (TRP) A1, a member of the TRP family of cation channels, was expressed in both DRG and nodose ganglion (NG) neurons innervating the stomach and in nerve fibers in the gastric wall. TRPA1 was coexpressed with ERK1/2 in gastric primary afferent neurons, and attenuation of TRPA1 activation using antisense peptides and a specific blocker led to suppression of both ERK1/2 activation and visceromotor responses. TRPA1 also significantly colocalized with substance P (SP) and calcitonin gene-related peptide (CGRP) in the thoracolumbar DRG, NG and stomach. These data indicate that SP and CGRP may also be released by TRPA1 activation in primary afferent neurons to elicit neurogenic inflammation and promote visceral hyperalgesia.
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PMID:Role of transient receptor potential A1 in gastric nociception. 2058 26

Growing evidence suggests a crucial involvement of extrinsic sensory neurons in the aberrant immune response in colitis. Activation of sensory neurons is accompanied by a release of the neuropeptides calcitonin gene-related peptide (CGRP) and substance P (SP), which induce neurogenic inflammation characterized by vasodilatation, plasma extravasation, and leukocyte migration. Although the role of these neuropeptides in experimental colitis and human inflammatory bowel disease (IBD) remains controversial, numerous data indicate a functional role for sensory neurons. In fact, chemical desensitization or surgical denervation of sensory nerves were shown to attenuate experimental colitis. Furthermore, pharmacological blockade of the neurokinin-1 (NK1) receptor was demonstrated to be efficient in chemically induced mouse models of colitis, and, intriguingly, also in immune-mediated models of colitis (T-cell transfer colitis). Finally, the genetic deletion or pharmacological blockade of receptor channels such as TRPV1 and TRPA1 on nociceptive sensory neurons was also demonstrated to be effective in treating experimental colitis, supposedly by inhibiting neuropeptide release. In summary, we are only beginning to understand the mechanisms of how sensory neurons modulate immune cellular actions. These findings highlight a new role of sensory neurons in chronic intestinal inflammation and suggest new avenues for therapy of IBD.
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PMID:Role of sensory neurons in colitis: increasing evidence for a neuroimmune link in the gut. 2072 67

The TRPA1 receptor is a member of the transient receptor potential (TRP) family of ion channels expressed in nociceptive neurons. TRPA1 receptors are targeted by pungent compounds from mustard and garlic and environmental irritants such as formaldehyde and acrolein. Ingestion or inhalation of these chemical agents causes irritation and burning in the nasal and oral mucosa and respiratory lining. Headaches have been widely reported to be induced by inhalation of environmental irritants, but it is unclear how these agents produce headache. Stimulation of trigeminal neurons releases CGRP and substance P and induces neurogenic inflammation associated with the pain of migraine. Here we test the hypothesis that activation of TRPA1 receptors is the mechanistic link between environmental irritants and peptide-mediated neurogenic inflammation. Known TRPA1 agonists and environmental irritants stimulate CGRP release from dissociated rat trigeminal ganglia neurons and this release is blocked by a selective TRPA1 antagonist, HC-030031. Further, TRPA1 agonists and environmental irritants increase meningeal blood flow following intranasal administration. Prior dural application of the CGRP antagonist, CGRP(8-37), or intranasal or dural administration of HC-030031, blocks the increases in blood flow elicited by environmental irritants. Together these results demonstrate that TRPA1 receptor activation by environmental irritants stimulates CGRP release and increases cerebral blood flow. We suggest that these events contribute to headache associated with environmental irritants.
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PMID:TRPA1 receptors mediate environmental irritant-induced meningeal vasodilatation. 2112 96

Peripheral inflammation initiates changes in spinal nociceptive processing leading to hyperalgesia. Previously, we demonstrated that among 102 lipid species detected by LC-MS/MS analysis in rat spinal cord, the most notable increases that occur after intraplantar carrageenan are metabolites of 12-lipoxygenases (12-LOX), particularly hepoxilins (HXA(3) and HXB(3)). Thus, we examined involvement of spinal LOX enzymes in inflammatory hyperalgesia. In the current work, we found that intrathecal (IT) delivery of the LOX inhibitor nordihydroguaiaretic acid prevented the carrageenan-evoked increase in spinal HXB(3) at doses that attenuated the associated hyperalgesia. Furthermore, IT delivery of inhibitors targeting 12-LOX (CDC, Baicalein), but not 5-LOX (Zileuton) dose-dependently attenuated tactile allodynia. Similarly, IT delivery of 12-LOX metabolites of arachidonic acid 12(S)-HpETE, 12(S)-HETE, HXA(3), or HXB(3) evoked profound, persistent tactile allodynia, but 12(S)-HpETE and HXA(3) produced relatively modest, transient heat hyperalgesia. The pronociceptive effect of HXA(3) correlated with enhanced release of Substance P from primary sensory afferents. Importantly, HXA(3) triggered sustained mobilization of calcium in cells stably overexpressing TRPV1 or TRPA1 receptors and in acutely dissociated rodent sensory neurons. Constitutive deletion or antagonists of TRPV1 (AMG9810) or TRPA1 (HC030031) attenuated this action. Furthermore, pretreatment with antihyperalgesic doses of AMG9810 or HC030031 reduced spinal HXA(3)-evoked allodynia. These data indicate that spinal HXA(3) is increased by peripheral inflammation and promotes initiation of facilitated nociceptive processing through direct activation of TRPV1 and TRPA1 at central terminals.
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PMID:Spinal 12-lipoxygenase-derived hepoxilin A3 contributes to inflammatory hyperalgesia via activation of TRPV1 and TRPA1 receptors. 2249 35


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