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

We cloned kappa and mu opioid receptor cDNAs. Using these cDNAs, first, we examined the molecular mechanism for the subtype selectivity of opioid ligands, especially a mu-selective ligand DAMGO. Binding experiments using various chimera and mutated receptors revealed that DAMGO discriminates between mu and delta receptors by recognizing the difference in only one amino acid residue, that is, N(127) in mu and K(108) in delta, at the first extracellular loop, and that it distinguishes between mu and kappa receptors by the difference in four amino acid residues at the third extracellular loop. Second, we established the cell lines expressing the cloned mu, delta, or kappa receptor and elucidated the pharmacological properties, that is, binding affinity and agonistic activity of several opioid agonists. Third, distribution of the mRNAs for mu, delta, and kappa receptors in the brain, spinal cord, and DRG was examined by in situ hybridization histochemistry (ISHH). Double ISHH demonstrated that most of the substance P-producing DRG neurons express the micro receptor. Recently, we are interested in the emotional aspect of pain and its regulation by opioids. Behavioral and microdialysis studies showed that sustained pain evoked by the intraplanter injection of formalin induced conditioned place aversion through the increment of glutamate release followed by the activation of NMDA receptors in the basolateral nucleus of amygdala (BLA). Intra-BLA injection of morphine suppressed the place aversion by inhibiting the glutamate release.
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PMID:[Molecular pharmacology of opioid receptors]. 1474 29

Upregulation of CGRP-immunoreactive (IR) primary afferent nerve fibers accompanied by mastocytosis is characteristic for the Schistosoma mansoni-infected murine ileum. These mucosal mast cells (MMC) and CGRP-IR fibers, which originate from dorsal root (DRG) and nodose ganglia, are found in close apposition. We examined interactions between primary cultured MMC and CGRP-IR DRG neurons in vitro by confocal recording of intracellular Ca(2+) concentration ([Ca(2+)](i)). The degranulatory EC(50) for the mast cell secretagogue compound 48/80 (C48/80; 10 microg/ml) and the neuropeptides CGRP (2.10(-8) M) and substance P (SP; 3.10(-8) M) were determined by measurement of extracellular release of the granule chymase, mouse mast cell protease-1. Application of C48/80 (10 microg/ml) and CGRP and SP (both 10(-7) M) to Fluo-4-loaded MMC induced a transient rise in [Ca(2+)](i) after a lag time, indicative of mast cell degranulation and/or secretion. The CGRP response could be completely blocked by pertussis toxin (2 microg/ml), indicating involvement of G(i) proteins. Application of MMC juice, obtained by C48/80 degranulation of MMC, to Fluo-4-loaded DRG neurons induced in all neurons a rise in [Ca(2+)](i), indicative of activation. Degranulation of MMC by C48/80 in culture dishes containing Fluo-4-loaded DRG neurons also caused activation of the DRG neurons. In conclusion, these results demonstrate a bidirectional cross-talk between cultured MMC and CGRP-IR DRG neurons in vitro. This indicates that such a communication may be the functional relevance for the close apposition between MMC and CGRP-IR nerve fibers in vivo.
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PMID:In vitro activation of murine DRG neurons by CGRP-mediated mucosal mast cell degranulation. 1501 15

Induction of cyclooxygenase-2 (COX-2) in the renal pelvic wall increases prostaglandin E(2) (PGE(2)) leading to stimulation of cAMP production, which results in substance P (SP) release and activation of renal mechanosensory nerves. The subtype of PGE receptors involved, EP2 and/or EP4, was studied by immunohistochemistry and renal pelvic administration of agonists and antagonists of EP2 and EP4 receptors. EP4 receptor-like immunoreactivity (LI) was colocalized with calcitonin gene-related peptide (CGRP)-LI in dorsal root ganglia (DRGs) at Th(9)-L(1) and in nerve terminals in the renal pelvic wall. Th(9)-L(1) DRG neurons also contained EP3 receptor-LI and COX-2-LI, each of which was colocalized with CGRP-LI in some neurons. No renal pelvic nerves contained EP3 receptor-LI and only very few nerves COX-2-LI. The EP1/EP2 receptor antagonist AH-6809 (20 microM) had no effect on SP release produced by PGE(2) (0.14 microM) from an isolated rat renal pelvic wall preparation. However, the EP4 receptor antagonist L-161,982 (10 microM) blocked the SP release produced by the EP2/EP4 receptor agonist butaprost (10 microM) 12 +/- 2 vs. 2 +/- 1 and PGE(2), 9 +/- 1 vs. 1 +/- 0 pg/min. The SP release by butaprost and PGE(2) was similarly blocked by the EP4 receptor antagonist AH-23848 (30 microM). In anesthetized rats, the afferent renal nerve activity (ARNA) responses to butaprost 700 +/- 100 and PGE(2).780 +/- 100%.s (area under the curve of ARNA vs. time) were unaffected by renal pelvic perfusion with AH-6809. However, 1 microM L-161,982 and 10 microM AH-23848 blocked the ARNA responses to butaprost by 94 +/- 5 and 78 +/- 10%, respectively, and to PGE(2) by 74 +/- 16 and 74 +/- 11%, respectively. L-161,982 also blocked the ARNA response to increasing renal pelvic pressure 10 mmHg, 85 +/- 5%. In conclusion, PGE(2) increases renal pelvic release of SP and ARNA by activating EP4 receptors on renal sensory nerve fibers.
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PMID:Activation of EP4 receptors contributes to prostaglandin E2-mediated stimulation of renal sensory nerves. 1529 51

Proinflammatory neuropeptides, such as substance P and calcitonin gene-related peptide, are up-regulated in primary afferent neurons in acute and chronic inflammation. While these neuropeptides have been intensively studied, potentially anti-inflammatory and/or anti-nociceptive neuropeptides such as somatostatin (SS) have been less widely investigated. Endogenous somatostatin is thought to exert a tonic antinociceptive effect. Exogenous SS is anti-inflammatory and antinociceptive and is thought to exert these actions through inhibition of proinflammatory neuropeptide release. In this study we have compared the expression of somatostatin in two inflammatory models: arthritis, a condition associated with increased nociception, and periodontitis, in which there is little evidence of altered nociceptive thresholds. In acute arthritis (< 24 h) SS mRNA was down-regulated in ipsilateral dorsal root ganglia (DRG; 52 +/- 7% of control, P < 0.05), and up-regulated in contralateral DRG (134 +/- 10% of control; P < 0.05). In chronic arthritis (14 days) this pattern of mRNA regulation was reversed, with SS being up-regulated ipsilaterally and down-regulated contralaterally. In chronic mandibular periodontitis (7-10 days), SS mRNA was up-regulated in only the mandibular division of the ipsilateral trigeminal ganglion (TG) (day 7, 219 +/- 9% and day 10, 217 +/- 12% of control; P < 0.02) but showed no change in other divisions of the trigeminal ganglion or in the mesencephalic nucleus. These data show that antinociceptive and anti-inflammatory neuropeptides are also regulated in inflammation. It is possible that the degree of inflammation and nociception seen may depend on the balance of pro- and anti-inflammatory and nociceptive peptide expression in a particular condition.
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PMID:Inflammation alters somatostatin mRNA expression in sensory neurons in the rat. 1565 50

The dorsal column pathway consists of direct projections from primary afferents and of ascending fibers of the post-synaptic dorsal column (PSDC) cells. This pathway mediates touch but may also mediate allodynia after nerve injury. The role of PSDC neurons in nerve injury-induced mechanical allodynia is unknown. Repetitive gentle, tactile stimulus or noxious pinch was applied to the ipsilateral hindpaw of rats with spinal nerve ligation (SNL) or sham surgery that had previously received tetramethylrhodamine dextran in the ipsilateral n. gracilis. Both touch and noxious stimuli produced marked increases in FOS expression in other cells throughout all laminae of the ipsilateral dorsal horn after nerve injury. However, virtually none of the identified PSDC cells expressed FOS immunofluorescence in response to repetitive touch or pinch in either the nerve-injured or sham groups. In contrast, labeled PSDC cells expressed FOS in response to ureter ligation and labeled spinothalamic tract (STT) cells expressed FOS in response to noxious pinch. Identified PSDC neurons from either sham-operated or SNL rats did not express immunoreactivity to substance P, CGRP, NPY, PKCY, MOR, the NK1 and the NPY-Y1 receptor. Retrogradely labeled DRG cells of nerve injured rats were large diameter neurons, which expressed NPY, but no detectable CGRP or substance P. Spinal nerve injury sensitizes neurons in the spinal dorsal horn to repetitive light touch but PSDC neurons apparently do not participate in touch-evoked allodynia. Sensitization of these non-PSDC neurons may result in activation of projections integral to the spinal/supraspinal processing of enhanced pain states and of descending facilitation, thus priming the central nervous system to interpret tactile stimuli as being aversive.
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PMID:Nerve injury-induced tactile allodynia is present in the absence of FOS labeling in retrogradely labeled post-synaptic dorsal column neurons. 1715 21

Aquaporin 1 (AQP1) is the archetypal member of a family of water channel proteins that contribute to water homeostasis in kidney, lung, and other tissues. Although there is limited evidence that aquaporins are expressed in the nervous system, AQP4 is expressed in glia and AQP9 is present on some neuronal and glial mitochondria. In the present study, we used immunohistochemistry to show that AQP1 is heavily expressed in a population of small diameter primary sensory neurons of dorsal root, trigeminal, and nodose ganglia. AQP1 immunoreactivity is abundant in DRG cell bodies and in both the peripheral and central branches of primary afferent neurons, and colocalizes with markers of nociceptors, notably substance P and IB4. AQP1 expression in DRG is first detectable at embryonic day 15.5, which corresponds to the developmental stage when the majority of fine cutaneous afferents penetrate the dorsal horn. Electron microscopy revealed dense membrane labeling of unmyelinated axons, a few fine diameter myelinated axons, and synaptic terminals in the superficial dorsal horn. Because this restricted and dense expression suggested that AQP1 contributes to nociceptive processing, we studied behavioral responses of wildtype and AQP1 -/- mice in a comprehensive battery of acute and persistent pain tests. We also used in vivo electrophysiology in wildtype and mutant mice to measure the responses of wide dynamic range neurons in lamina V of the dorsal horn to thermal stimulation before and after noxious stimulus-induced sensitization. To date we have not detected a differential phenotype suggestive of a functional contribution of AQP1 to nociceptive processing.
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PMID:Anatomical and functional analysis of aquaporin 1, a water channel in primary afferent neurons. 1725 50

This work was aimed at the morphological and biochemical characterisation of the most susceptible neuronal subpopulation to rabies virus (RABV) infection. Adult mouse DRG cultures were infected with RABV and double-processed for viral antigen detection and neuropeptides: calcitonin gene-related peptide (CGRP), galanin (GAL), substance P (SP), neuropeptide Y (NPY) and vasoactive intestinal peptide (VIP). It was found that 56% of the neurons in culture were small (diameter < 20 microm) but, in spite of this, 69% of the infected neurons had intermediate and large diameters (> or = 20 microm). More than 50% of infected neurons expressed NPY, VIP or SP, whereas no association was found between infected neurons and the presence of CGRP or GAL. Despite SP having been shown to be a small neuron marker, it was found that RABV infects medium and large-sized SP positive cells. RABV preference for larger neurons could explain part of the neuropathogenesis since it can be suggested that, following a rabid accident, the virus uses large neurons (mainly innervating muscle and joints) in vivo to be transported later on to the central nervous system.
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PMID:Morphological and biochemical characterisation of sensory neurons infected in vitro with rabies virus. 1744 Jul 42

The mechanism underlying discogenic low-back pain is unclear. It is difficult to explain this type of pain by the segmental innervation theory because the groin area is innervated by the genitofemoral or ilioinguinal nerves, which are the terminal branches of the L1 or L2 spinal nerves. Recently, some studies have indicated that sympathetic trunks are closely related to discogenic low-back pain. However, sympathetic trunk resection can severely affect the function of the abdominal organs and lower extremities and may cause retrograde ejaculation in human beings. This study was initiated to evaluate the role of selective transection of the L2 ramus of the nociceptive pathway in the lumbar intervertebral discs in rats, by using the fluorogold (FG) retrograde transport method and immunohistochemistry of substance P (SP). Of the FG-labeled neurons in the L2 and L5 dorsal root ganglia (DRGs), the cross-sectional area of the SP-immunoreactive (ir) neurons ranged from 210 to 1140 microm(2); the mean cross-sectional area was 652+/-320 microm(2). We demonstrated that FG-labeled SP-ir neurons in L2 DRGs decreased when FG was applied to the ventral or dorsal portions of L5-6 discs. The results indicated that the L2 ramus communicans played an important role in the afferent pathway of both the ventral and dorsal portions of the L5-6 disc. Nociceptive information from the L5-6 disc may be transmitted mainly by L2 DRG neurons through the L2 ramus communicans.
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PMID:Effect of the L2 ramus communicans on the nociceptive pathway in lumbar intervertebral discs in rats. 1824 22

Ralfinamide is analgesic when applied as a single dose in rodent models of stimulus-evoked chronic pain. However, it is unknown whether its chronic application after nerve injury can suppress spontaneous chronic pain, the main symptom driving patients to seek treatment. In this study ralfinamide was administered to rats at doses producing plasma levels similar to those causing analgesia in pain patients. The analgesic effect was tested on autotomy, a behavior of self-mutilation of a denervated paw that models spontaneous neuropathic pain. Sprague-Dawley male rats (N=10-20/group) underwent transection of the sciatic and saphenous nerves unilaterally. Ralfinamide or its vehicle were administered per os for 7 days preoperatively (80 mg/kg; bid), followed by the vehicle or Ralfinamide, until postoperative d42. Autotomy was scored daily until d63. Lasting 'preemptive analgesia' was found in rats treated with ralfinamide preoperatively, expressed by delayed autotomy onset (P=0.009) and reduced scores on d63 (P=0.01). Rats treated with ralfinamide (30 or 60 mg/kg; bid) from the operation till d42, but not preoperatively, also showed delayed autotomy (P=0.05, P=0.006), and reduced autotomy scores lasting till d63 (P=0.02, P=0.01), for the two doses, respectively. Combining ralfinamide treatments for 7 days preoperatively and 42 days postoperatively also resulted in significantly suppressed scores on d42 and d63 (P=0.005, P=0.001, respectively). Suppression of neuropathic pain-related behavior was likely caused by a combination of mechanisms reported for ralfinamide, including inhibition of Na+ and Ca++ currents in Nav1.3, Nav1.7, Nav1.8, and Cav2.2 channels in rat DRG neurons, inhibition of substance P release from spinal cord synaptosomes, NMDA receptor antagonism and neuroprotection.
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PMID:Ralfinamide administered orally before hindpaw neurectomy or postoperatively provided long-lasting suppression of spontaneous neuropathic pain-related behavior in the rat. 1858 49

The present study was conducted to determine whether the activation of neurokinin-1 receptor (NK-1R) by its agonist (GR73632) enhances the capsaicin-evoked substance P (SP) release using a radioimmunoassay. A pre-exposure to GR73632 enhanced the capsaicin-evoked SP release in a time- and dose-dependent manner. The augmentation of capsaicin-evoked SP release by GR73632 was completely inhibited by pharmacological blockade of NK-1R or transient receptor potential vanilloid receptor subtype 1 (TRPV1), and was partially attenuated by the inhibition of either protein kinase C (PKC), cyclooxygenase (COX) or phospholipase C (PLC), p38 or p42/44 mitogen-activated protein (MAP) kinase, but not protein kinase A. This augmentation of SP release was further increased by inhibition of c-Jun NH2-terminal kinase. A short-term (10min) exposure to GR73632 resulted in an increase in the TRPV1 phosphorylation. The increase in the TRPV1 phosphorylated forms induced by a 60-min exposure to GR73632 was completely abolished by the inhibition of either PKC, COX or PLC, p38 or p42/44 MAP kinases. Immunocytochemistry study demonstrated that the NK-1R and TRPV1 were mainly co-expressed in the small-sized neurons. These findings suggest that the activation of NK-1R by its agonist, by sensitizing the TRPV1 through the PKC phosphorylation of TRPV1, may play a role in the enhancement of the capsaicin-evoked SP release from cultured rat DRG neurons.
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PMID:Phosphorylation of TRPV1 by neurokinin-1 receptor agonist exaggerates the capsaicin-mediated substance P release from cultured rat dorsal root ganglion neurons. 1880 16


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