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)

Understanding pain or, more precisely, the different types of pain, is above all a question of understanding its physiological mechanisms and, in this regard, the role of basic research has without doubt been to trigger the development of new therapeutic strategies. In an approach to these problems, the main international teams involved in pain research have attempted to develop models of experimental pain in rats. Clearly, research aimed at developing these models is controlled by certain ethical considerations; however, in this context, the end must surely justify the means. The main models used (acute or chronic inflammation, rheumatoid arthritis, peripheral neuropathy) certainly do not give a comprehensive representation of all the pain syndromes encountered in clinical practice, but they do provide new data concerning the physiological, behavioural and pharmacological aspects of pain. While giving a brief description of the complexity of the pain circuit, this article also makes reference to certain pharmacological approaches to the treatment of pain. Peripheral nociceptive messages are conveyed by a mosaic of unmyelinated free fibres distributed throughout cutaneous, muscular and articular tissue, and within the visceral walls. They are then transmitted via various nerve endings (polymodal nociceptors) by small diameter A delta and C fibres, which are activated by mechanical, thermal and chemical stimuli. It is nevertheless difficult to ascertain whether these small diameter fibres are involved only in nociception (specific nociceptors) or whether pain causes an excessive activation of these receptors, which under normal conditions have a role in the reflex that regulates various functions (nonspecific nociceptors). Numerous chemical substances play a part in generating nociceptive impulses (e.g. histamine, serotonin, prostaglandins). Furthermore, the role of neuropeptides, such as calcitonin gene-related peptide and particularly substance P, has been clearly demonstrated in the activation of early neurogenic inflammation. Other substances, such as bradykinin and cytokines, are involved in prolonging the sensation of pain. Nerve growth factor also prolongs the sensation of pain by increasing the cellular excitability of nociceptors and promoting the action of the sympathetic nervous system, which has a major role in controlling pain. The very great diversity of all these interacting substances makes the pharmacological treatment of pain extremely complex. Nevertheless, new therapeutic advances are providing interesting approaches, particularly the development of specific inhibitors of cyclo-oxygenase 2 (COX 2), which is produced by the inflammatory process. Such inhibitors would preserve COX 1, which is both constitutive and physiological, and thereby provide improved tolerability compared with currently used NSAIDs, which act upon both COX pathways. A major focus of research relating to new analgesics is the development of synthetic antagonists of bradykinin, substance P and N-methyl-D-aspartate receptors. An improved understanding of anatomical and electrophysiological processes has led to the discovery of new ascending pathways that transmit nociceptive messages to the reticular formation, the hypothalamus, and the amygdala, as well as to certain areas of the cortex. As a result the notion of one single pain centre is no longer valid. This idea is further reinforced by the knowledge that, at different stages of the pain pathway, different control systems constantly modulate the transmission of nociceptive information. Consequently, at a spinal level, activation of the large diameter cutaneous fibres (A alpha et beta) blocks pain stimuli transmitted by the small diameter fibres. Knowledge of this "gate control' mechanism of the posterior horn of the spinal cord is put to practical application in treatments involving transcutaneous electrical nerve stimulation. (ABSTRACT TRUNCATED)
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PMID:[The complexity of physiopharmacologic aspects of pain]. 919 Mar 19

Since serotonin (5-HT) is implicated in exacerbating acute coronary syndromes, we studied the reactivity of atrial coronary arterioles (70-140 microm) of atherosclerotic patients undergoing cardiac surgery to 5-HT, substance P (Sub P), and sodium nitroprusside by video-microscopy. Before ischemia, 5-HT-induced relaxation was not affected by NS398 (cyclooxygenase inhibitor), H2O2 or U63557A (thromboxane A2 synthase inhibitor), but was reduced by L-NNA. 5-HT elicited a potent contractile response after ischemia that was inhibited by NS398, Indo, and U63557A. While Sub P relaxation was decreased after ischemia, SNP relaxation was unchanged. The mRNA steady-state levels of NOS-3, NOS-2, prostacyclin synthase, and COX- 1 were not altered by ischemia. COX-2 mRNA and protein levels (Westernblotting), however, were increased (mean +/- SEM) 2.4 +/- 0.4 and 3.2 +/- 0.7 fold, respectively, in ischemic atrium corroborating with the immunohistochemistry of atrial tissue. It is concluded that myocardial ischemia enhanced contractile response of coronary arterioles to 5-HT maybe due to the stimulated prostaglandin release (likely thromboxane A2) secondary to induction of COX-2 expression. These findings may have implications regarding the cause of coronary spasm during acute myocardial ischemia.
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PMID:Serotonin-induced human coronary microvascular contraction during acute myocardial ischemia is blocked by COX-2 inhibition. 1121 33

During inflammatory states, airway epithelial cells are stimulated by various proinflammatory mediators to synthesize paracrine mediators including prostaglandin E2, which likely contributes to the recurrence of allergic inflammation. We studied the effects of acetylcholine (ACh) and substance P (SP) on PGE2 release because these two neuromediators are widely involved in airway inflammation, e.g., to trigger mucosal vasodilation and plasma exudation. PGE2 release was studied at baseline and after addition of ACh and SP (10(-10) to 10(-7) M) in primary cultures of human nasal epithelial cells from control mucosa, inflammatory non-atopic mucosa, and inflammatory atopic mucosa. The mediators' effects on COX 2 mRNA were assessed by Northern blotting. We also tested the effect of atropine and SR140333, inhibitors of ACh and SP, respectively. The spontaneous release of PGE2 was about three times higher in cells from atopic subjects. ACh and SP markedly increased PGE2 release (by more than 1.5 times) and this effect was similar whether the sampled tissues were inflammatory or not. In cells from atopic subjects this neuromediator effect led to a fivefold increase in PGE2 release, as compared to baseline production by cells from control mucosa. This stimulation of PGE2 release by neural mediators was inhibited by specific antagonists. ACh and SP increased COX 2 mRNA in the three groups. Thus, neuromediators can bolster PGE2 production in the airway, likely reinforcing inflammation. In conclusion, these data provide evidence that the interplay of nerve fibers and airway epithelial cells is likely important in inflammatory conditions as, e.g., allergy and asthma.
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PMID:Neural-epithelial cell interplay: in vitro evidence that vagal mediators increase PGE2 production by human nasal epithelial cells. 1122 12

We previously reported that partial sciatic nerve ligation (PSNL) dramatically up-regulates cyclooxygenase 2 (COX2) in injured sciatic nerve, and local injection of the COX inhibitor, ketorolac, reverses tactile allodynia and suppresses increased phosphorylation of the transcription factor cAMP responsive element binding protein [Eur J Neurosci 15 (2002) 1037]. These findings suggest that peripheral prostaglandins (PGs) are over-produced and contribute to the central plasticity and the maintenance of neuropathic pain after nerve injury. PGs, particularly PGE2, are well known to facilitate the release of the pro-nociceptive neuropeptide substance P (SP) and calcitonin gene-related peptide (CGRP) from primary sensory afferents. Thus, suppressing peripheral PG over-production may inhibit the release of these two neuropeptides from primary afferents and thereby increase the content of these neuropeptides remaining in afferent terminals in the dorsal horn. In this study we tested this hypothesis by examining the immunoreactivities of SP and CGRP in the dorsal horn of PSNL rats intraplantarly injected with saline and ketorolac. Four weeks after PSNL, SP- and CGRP-immunoreactivities (IR) in the ipsilateral dorsal horn were not significantly different from the contralateral side. Five days following intraplantar injection of ketorolac, CGRP- and SP-IR in the ipsilateral and contralateral dorsal horn were dramatically reduced compared with saline-injected PSNL rats. Local ketorolac also suppressed PSNL-induced increase in dynorphin-IR in dorsal horn neurons. Since abundant production of PGs during inflammation is well documented, we further examined the effect of intraplantar ketorolac on neuropeptide expression in the dorsal horn following carrageenan inflammation. We observed that co-administration of ketorolac with carrageenan in the hindpaw also reduced SP- and dynorphin-IR in the ipsilateral and contralateral dorsal horn. These findings are in contrast to our hypothesis, suggesting that peripherally over-produced PGs following nerve injury and inflammation possibly contribute to the production of SP and CGRP in primary sensory neurons, to the up-regulation of dynorphin in the dorsal horn neurons, and finally to the mechanisms of neuropathic and inflammation pain.
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PMID:Intraplantar injection of a cyclooxygenase inhibitor ketorolac reduces immunoreactivities of substance P, calcitonin gene-related peptide, and dynorphin in the dorsal horn of rats with nerve injury or inflammation. 1456 28

Irritable bowel syndrome (IBS) is one of several functional gastrointestinal disorders commonly encountered in both the clinical setting and the general population. The biopsychosocial model is currently believed to be a more complete explanatory mechanism of IBS symptom genesis and propagation. Gut inflammation and immune activation is one of the biological mechanisms for which evidence is emerging. Experimental parasitic infection of mice bowel resulted in elevated substance P levels and increased expression of cyclooxygenase 2 (COX 2) enzyme, prostaglandin E2, IL-4, IL-5, and IL-13. In IBS patients, increased cellularity and proximity of the inflammatory or immune cells to the nerve trunks of the bowel, elevated interleukin-1beta mRNA expression in mucosal biopsies, and increased inducible nitric oxide synthase and nitrotyrosine elaboration (indicative of lymphocyte activation) were observed. Corticosteroids given after the elimination of an experimentally applied parasite from the bowel of mice resulted in the reversal of persistent gut muscle dysfunction. Selective COX-2 inhibitors attenuated the increased bowel smooth muscle contractility resulting from parasite infection of mice gut. In humans, it has been observed that the relative risk of developing IBS in asthma patients was reduced by 60% by the use of oral steroids. Despite such preclinical and human evidence for the role of inflammation and immune activation in IBS, the efficacy of anti-inflammatory and immunomodulatory agents has not been adequately investigated. Budesonide, a corticosteroid with a high mucosal activity and a low bioavailability, is an anti-inflammatory agent that may be worth investigating for its utility in diarrhea-predominant IBS.
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PMID:Will corticosteroids and other anti-inflammatory agents be effective for diarrhea-predominant irritable bowel syndrome? 1589 25

Mast cells play an important role in both innate and acquired immunity as well as several pathological conditions including allergy, arthritis and neoplasia. They influence these processes by producing a variety of mediators including cytokines, chemokines and eicosanoids. Very little is currently known about the spectrum of inflammatory mediators, particularly eicosanoids (prostaglandins and leukotrienes), produced by canine mast cells. This is important since modulating mast cell derived eicosanoids may help in the treatment of autoimmune and inflammatory disorders. The purpose of this study was to investigate the spectrum of eicosanoids produced by normal canine mast cells and to evaluate the effects of cytokines and non-steroidal anti-inflammatory mediators (NSAIDS) on eicosanoid production and release. Canine bone marrow derived cultured mast cells (cBMCMCs) expressed COX-1, COX-2, and 5-LOX and synthesized and released PGD2, PGE2, LTB4, and LTC4 following activation by a variety of stimuli. The selective COX-2 NSAIDs carprofen (Rimadyl) and deracoxib (Deramaxx) inhibited PGD2 and PGE2 production but only slightly inhibited LTB4 and LTC4. The mixed COX-1/COX-2 inhibitor piroxicam blocked PGD2 and PGE2 production, but upregulated LTC4 following treatment while tepoxilan (Zubrin), a pan COX/LOX inhibitor, markedly reduced the production of all eicosanoids. The LOX inhibitor nordihydroguaiaretic acid (NDGA) prevented LTB4/LTC4 release and BMBMC degranulation. Pre-incubation of cBMCMCs with IL-4 and SCF sensitized these cells to degranulation in response to substance P. In conclusion, canine BMCMCs produce an array of eicosanoids similar to those produced by mast cells from other species. Tepoxilan appeared to be the most effective NSAID for blocking eicosanoid production and thus may be useful for modulating mast cell mediated responses in dogs.
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PMID:Characterization and modulation of canine mast cell derived eicosanoids. 2003 14

Targeting analgesic drugs for spinal delivery reflects the fact that while the conscious experience of pain is mediated supraspinally, input initiated by high intensity stimuli, tissue injury and/or nerve injury is encoded at the level of the spinal dorsal horn and this output informs the brain as to the peripheral environment. This encoding process is subject to strong upregulation resulting in hyperesthetic states and downregulation reducing the ongoing processing of nociceptive stimuli reversing the hyperesthesia and pain processing. The present review addresses the biology of spinal nociceptive processing as relevant to the effects of intrathecally-delivered drugs in altering pain processing following acute stimulation, tissue inflammation/injury and nerve injury. The review covers i) the major classes of spinal agents currently employed as intrathecal analgesics (opioid agonists, alpha 2 agonists; sodium channel blockers; calcium channel blockers; NMDA blockers; GABA A/B agonists; COX inhibitors; ii) ongoing developments in the pharmacology of spinal therapeutics focusing on less studied agents/targets (cholinesterase inhibition; Adenosine agonists; iii) novel intrathecal targeting methodologies including gene-based approaches (viral vectors, plasmids, interfering RNAs); antisense, and toxins (botulinum toxins; resniferatoxin, substance P Saporin); and iv) issues relevant to intrathecal drug delivery (neuraxial drug distribution), infusate delivery profile, drug dosing, formulation and principals involved in the preclinical evaluation of intrathecal drug safety.
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PMID:Current and Future Issues in the Development of Spinal Agents for the Management of Pain. 2686 70