Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030193 (pain)
 261,466 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the present article special interest has been focused on indicators of latent and manifest pulpal inflammation studied by psychophysical and electrophysiological techniques. Intradental A-delta nerve activity was recorded from two electrodes placed in the dentin on the labial tooth surface. The psychophysical measures were obtained by means of direct scaling methods in combination with sensory verbal descriptors. For stimulation cooling (ethyl chloride) and heating (hot guttapercha) of the tooth surface were employed. In addition, potentially algogenic substances, bradykinin and histamine, were administered on partly exposed pulps. Hot guttapercha induced a more complex neural response pattern than ethyl chloride. In all the recordings the responses evoked by heat showed a characteristic pattern consisting of three phases: an initial phase of short duration (i) followed by a depression in activity relative to the baseline (ii) and a slow spontaneously emerging activity in the absence of a physical stimulus (iii). The latter neutral event (iii) passed unnoticed by all the subjects. In the light of earlier experiments on feline pulp it was hypothesized that this third phase of the neural response was an indication of hyperexcitability in dental pulps and thus inflammation. Those subjects who experienced pulsating, dull, lingering pain (clinically diagnosed as pulpitis) showed a poor correlation between magnitude estimates of their mixed pain percepts and the total flux of A-delta nerve activity. Bradykinin and histamine evoked dull pain in the majority of cases probably caused by excitation of pulpal C fibers. In one experiment A-delta neural discharge of short duration could also be triggered by histamine.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Inflammation and dental pain in man. 784 60

Bradykinin is a nonapeptide that plays a central role in the production of pain and inflammation. A horizontal spinal cord slice preparation with attached dorsal root and dorsal root ganglion was used to study the effect of bradykinin on afferent fibers. Intracellular recordings were made from dorsal root ganglion and dorsal horn neurons. Bath application of bradykinin (1 microM) to the dorsal root ganglion compartment produced a depolarization (5 +/+ 0.8 mV) and firing of action potentials in eight out of eighteen dorsal root ganglion neurons tested. Simultaneous intracellular recordings from dorsal horn neurons revealed that the application of bradykinin to dorsal root ganglion, peripheral nerve trunk or dorsal root resulted in the synaptic activation of dorsal horn neurons. The depolarizing effect of bradykinin on the dorsal root ganglion neurons and its synaptic excitatory effect on dorsal horn neurons was abolished by pretreatment of the same segment of sensory neurons by a B2 bradykinin receptor antagonist (D-Arg0,Hyp3,beta-Thi5,8,D-Phe7)-bradykinin (5 microM). Bath application of tetrodotoxin (TTX; 0.2-1 microM) to the sensory neurons blocked electrically-evoked action potentials in large dorsal root ganglion neurons and, consequently, excitatory postsynaptic potentials in dorsal horn neurons evoked by electrical activation of low threshold afferent fibers. However, the stimulatory effects, both depolarization and firing of action potentials, of bradykinin were resistant to TTX. Replacement of sodium ions with TRIS completely abolished the stimulatory effect of bradykinin on the sensory neurons. Bradykinin potentiated the postsynaptic potentials induced by electrical stimulation of TTX-resistant afferent fibers.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Bradykinin excites tetrodotoxin-resistant primary afferent fibers. 788 21

Bradykinin (BK) is a peptide hormone with sequence Arg1-Pro2-Pro3-Gly4-Phe5-Ser6-Pro7-Phe8-Arg9 and has been implicated in a multitude of pathophysiological processes such as the ability to lower systemic blood pressure and stimulate pain. Bulky, beta-branched D-aliphatic residues at position 7 combined with bulky L-aliphatic residues at position 8 have now been observed to yield strong antagonists. Nuclear magnetic resonance studies have been carried out on many of these molecules with a view to determining their solution conformations. However, two such analogs, namely DArg-[Hyp3, Thi5, DSer6, DCpg7, Cpg8]-BK [I] and DArg-[Hyp3, DSer6, DCpg7, Cpg8]-BK [II] (Cpg = alpha-cyclopentyl-glycine; Hyp = 4-hydroxy-L-proline, Thi = beta-(2-thienyl)-L-alanine), have exhibited an abnormal, non-linear temperature dependence for the amide NH proton of Cpg8. The NH of Arg9 also shows a slightly non-linear temperature dependence at higher temperatures above 25 degrees C. In addition, a very slow exchange rate for the NH protons of DCpg7, Cpg8 and Arg9 indicated aggregation of these two analogs, which was confirmed using the circular dichroism experiments.
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PMID:The aggregation properties of some bradykinin analogs. 821 42

Bradykinin (BK) is a peptide hormone with sequence Arg1-Pro2-Pro3-Gly4-Phe5-Ser6-Pro7-Phe8-Arg9 and has been implicated in a multitude of pathophysiological processes such as the ability to lower systemic blood pressure and stimulate pain. BK analogues having bulky, beta-branched D-aliphatic residues at position 7 combined with bulky L-aliphatic residues at position 8 have now been observed to be strong antagonists. Conformational studies based on two-dimensional nmr experiments in methanol/water (80/20 v/v) were carried out on several such active antagonists in a polar solvent. Included in this study were the very active antagonists, [D-Arg0,Hyp3,Thi5,D-Cpg7,Cpg8]-BK [Cpg: alpha-cyclo-pentyl-glycine; Hyp: trans-4-hydroxy-L-proline; Thi: beta-(2-thienyl)-L-alanine] (I), [D-Arg0,Hyp3,D-Cpg7,Cpg8]-BK (II), as well as its variant with D-Cpg7 replaced by Cpg7, namely [D-Arg0,Hyp3,Cpg7,Cpg8]-BK (III). A turn-like structure, which coexists with the extended conformation, was observed between residues 2 and 5 for the most active antagonists I and II, in direct correlation with the peptide activities. No turn-like structure was found for residues 6-9. In peptide III, a turn-like structure was not identified. The existence of a turn at the C-terminal end of bradykinin and its analogues has been predicted by empirical calculations and supported by nmr measurements. But the present nmr study on the most active antagonists (I, II) does not support this hypothesis. Instead, the data suggest that a turn-like structure between residues 2 and 5 could be important for antagonist activity. Finally, one weak inhibitor [D-Cpg7]-BK (IV) showed no defined secondary structure.
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PMID:Proton magnetic resonance studies of bradykinin antagonists. 836 57

1. Bradykinin and related kinins may act on four types of receptors designated as B1, B2, B3 and B4. It seems that the B2 receptors are most commonly found in various vascular and non-vascular smooth muscles, whereas B1 receptors are formed in vitro during trauma, and injury, and are found in bone tissues. 2. These BK receptors are involved in the regulations of various physiological and pathological processes. 3. The mode of kinin actions are based upon the interactions between the kinin and their specific receptors, which can lead to activation of several second-messenger systems. 4. Recently, numerous BK receptors antagonists have been synthesized with prime aim to treat diseases caused by excessive kinin production. 5. These diseases are RA, inflammatory diseases of the bowel, asthma, rhinitis and sore throat, allergic reactions, pain, inflammatory skin disorders, endotoxin and anaphylactic shock and coronary heart diseases. 6. On the other hand, BK receptor antagonists could be contraindicated in hypertension, since these drugs may antagonize the antihypertensive therapy and/or may trigger the hypertensive crisis. 7. It is worth suggesting that the BK receptor agonists might be useful antihypertensive drugs.
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PMID:Therapeutic prospects of bradykinin receptor antagonists. 838 49

While B2 receptors mediate pain and hyperalgesia induced by bradykinin, in normal rats, recent reports indicate that, in the setting of inflammation, B1 receptors also mediate pain and hyperalgesia. Since bradykinin-induced hyperalgesia in normal rats is mediated by prostaglandins released from the postganglionic sympathetic neurons, we have evaluated the contribution of the sympathetic nervous system to the hyperalgesia induced by bradykinin, a preferential B2-receptor agonist, and des-Arg9-bradykinin, a major metabolite of bradykinin and a selective B1-receptor agonist. Mechanical hyperalgesia was quantified by the Randall-Selitto paw-withdrawal method. Inflammation was induced by injecting Complete Freund's Adjuvant into the left hindpaw of the rat and testing mechanical nociceptive threshold in the right hindpaw after injecting B1 or B2 agonists and/or antagonists. Sympathectomy was achieved by surgically removing sympathetic ganglia L1-L4. Rats were used 48 h post-adjuvant injection. In the normal rat, intradermal injection of bradykinin but not des-Arg9-bradykinin, into the dorsal surface of the hindpaw, produced a dose-dependent decrease in mechanical nociceptive threshold. NPC 17731, a B2-receptor antagonist, but not des-Arg9-[Leu8]-bradykinin, a B1-receptor antagonist, almost completely inhibited the decrease in mechanical threshold, suggesting that bradykinin hyperalgesia in the normal rat hindpaw was mediated by B2 receptors. In rats whose left paws were treated, 48 h earlier, with adjuvant, intradermal injection of bradykinin or des-Arg9-bradykinin, into the right paw produced dose-dependent hyperalgesia. Bradykinin hyperalgesia was partially inhibited by NPC 17731, and the residual part by des-Arg9,[Leu8]-bradykinin. des-Arg9-bradykinin hyperalgesia was inhibited by des-Arg9,[Leu8]-bradykinin but not by NPC17731. These results suggest that in the setting of inflammation, bradykinin hyperalgesia was mediated by both B1 and B2 receptors, and that des-Arg9-bradykinin hyperalgesia was mediated by the B1 receptor. Forty-eight hours after injection of complete Freund's adjuvant, in sympathectomized rats, bradykinin or des-Arg9-bradykinin failed to produce hyperalgesia, suggesting that intact sympathetic postganglionic neurons are required for the hyperalgesia produced by these agents in this model. These results are consistent with the suggestions that B2 receptors mediate bradykinin-induced cutaneous hyperalgesia in the normal rat hindpaw. The hyperalgesia induced by bradykinin, 48 h post injection of complete Freund's adjuvant is mediated by both B1 and B2 receptors, that by des-Arg9-bradykinin is mediated by B1 receptors. The hyperalgesia induced by both agents is dependent on the presence of intact sympathetic postganglionic neurons.
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PMID:Inflammation modulates the contribution of receptor-subtypes to bradykinin-induced hyperalgesia in the rat. 855 60

Previous studies show that oral antihistamines affect the weal and flare response to intradermal injections of the inflammatory mediators platelet-activating factor (PAF) and bradykinin (BK). The aim of this study was to compare the effects of terfenadine (an H1-antagonist) and cimetidine (an H2-antagonist) on weal and flare responses to PAF and BK in healthy non-atopic human volunteers. The effects of doxepin on PAF responses were investigated, as there is evidence that doxepin may have direct anti-PAF effects in addition to its known antihistaminic actions. Terfenadine significantly reduced weal and flare responses to PAF (mean reduction 53 and 73%, respectively) and flare responses to BK (mean reduction 78%) but had no effect on weal responses to BK. Doxepin significantly reduced both weal and flare responses to PAF (mean reduction 43 and 68%, respectively, at higher doses of PAF). Cimetidine had no effect on weal or flare responses to PAF or BK. These findings suggest that the flare response to intradermal BK is mediated via histamine release while the weal response is not. The effects of the various antagonists of PAF-induced responses suggest that its effects too may be mediated via histamine, the similarity of the effects of terfenadine and doxepin on these responses indicating that the effects of doxepin may be due to its known antihistamine activity rather than to any specific PAF-antagonistic properties. Platelet-activating factor (PAF) is a phospholipid which is released from a wide range of cell types and also from vascular endothelium. PAF is formed by the conversion of ether-linked phospholipids initially to the biologically inactive lyso-PAF and then by acetylation to PAF. Intradermal injection of PAF in human skin causes vasodilatation and increased vascular permeability, producing a weal and flare response with accompanying pruritus. Bradykinin (BK) is a vasoactive polypeptide formed by the action of enzymes known as kallikreins on inactive precursors called kininogens. Its effects include an increase in blood flow and vascular permeability and stimulation of the release of prostaglandins and histamine. On intradermal injection in human skin it causes a weal and flare response with associated pain rather than pruritus. Previous studies have suggested that the weal and flare response to PAF may be mediated in part by histamine release. Given that BK is known to cause histamine release it appears possible that the responses to both compounds may be modified by conventional antihistamines. Experiments based on this premise have found that antihistamines have a pronounced effect on the flare response to PAF but a less marked effect on weal responses. The weal response to BK was unaffected by systemic antihistamines but studies have produced conflicting results with regard to effects on the flare response. The aim of this study was to compare the effects of terfenadine (an H1-antagonist) and cimetidine (an H2-antagonist) on PAF- and BK-induced weal and flare responses in healthy, non-atopic human volunteers. Based on the treatment of cold urticaria it has been suggested that doxepin, which has known H1- and H2-antagonistic effects, may in addition show specific anti-PAF activity. We compared the effects of doxepin on PAF-induced intradermal responses with those of terfenadine and cimetidine in this study.
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PMID:Effects of H1- and H2-antihistamines on platelet-activating factor and bradykinin-induced inflammatory responses in human skin. 868 66

1. Bradykinin-induced vascular pain in conscious rats, hyperalgesia in the rat hind paw, rat hind paw edema induced by compound 48/80 and carrageenin and dye exudation induced by intraperitoneal injection of 0.7% acetic acid in mice were all inhibited by sodium nonivamide acetate (SNA). 2. Collagen and arachidonic acid-induced rabbit platelet aggregations were inhibited by SNA and capsaicin. In human platelet microsomes, prostaglandin E2 formation in arachidonic acid metabolite was not inhibited by SNA but was inhibited by capsaicin and indomethacin; thromboxane B2 formation and its synthetase activity were inhibited by SNA and capsaicin. 3. In the extracellular recording, SNA could not decrease the action potential amplitude of the vagus nerve. 4. The motor activity of mice induced by caffeine (1.0 mg/kg) was inhibited by SNA and capsaicin.
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PMID:Sodium nonivamide acetate: a non-pungently antinociceptive capsaicin derivative with unusual anti-inflammatory properties. 874 12

Bradykinin may be generated in the heart during ischemia and is involved in nociception. We tested the hypothesis that bradykinin elicits a sympathoexcitatory reflex in rats by stimulating cardiac afferent nerve fibers. Rats were implanted with femoral catheters for measurement of blood pressure and heart rate, a bipolar electrode for measurement of renal sympathetic nerve activity, and a pericardial catheter for intrapericardial injection of substances. Rats were slightly anesthetized with hexobarbital so pain reactions were prevented. Graded doses of bradykinin (2.5, 12, 25 micrograms) were injected intravenously or intrapericardially into control rats, intrapericardially after vagotomy, intrapericardially after intrapericardial pretreatment with the bradykinin B2 receptor antagonist Hoe 140, and intrapericardially after cardiac autonomic blockade (intrapericardial pretreatment with 10% procaine). For comparison, the serotonin 5-HT3 agonist phenylbiguanide, a substance known to elicit sympathoinhibitory reflexes by cardiac vagal afferents, and adenosine, putatively inducing sympathoexcitatory responses via the heart, were applied intrapericardially. Bradykinin increased blood pressure when administered intrapericardially but decreased blood pressure when injected intravenously; both intrapericardial and intravenous bradykinin increased renal sympathetic nerve activity. Intrapericardial adenosine had no effect on circulatory control. Intrapericardial pretreatment with the B2 receptor antagonist Hoe 140 completely inhibited the increases of blood pressure and renal sympathetic nerve activity in response to intrapericardial bradykinin but did not affect the responses to intrapericardial phenylbiguanide. Bilateral cervical vagotomy abolished the decreases of blood pressure, heart rate, and renal sympathetic nerve activity after intrapericardial phenylbiguanide but did not influence the responses to intrapericardial bradykinin. Cardiac autonomic blockade with intrapericardial procaine abolished all responses to bradykinin and phenylbiguanide. We conclude that cardiac bradykinin elicits a sympathoexcitatory reflex by epicardial B2 receptors in rats. The afferent portion of the reflex is most likely contained within sympathetic cardiac afferent fibers. Bradykinin may contribute to increased sympathetic nerve activity in pathophysiological situations of coronary artery disease and cardiac ischemia.
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PMID:Epicardial bradykinin B2 receptors elicit a sympathoexcitatory reflex in rats. 884 87

Bradykinin (BK) and Tyr8-BK induced graded rat paw edema with EC50 values of 1.9 and 1.1 nmol/paw, while des-Arg9-BK (DABK, up to 300 nmol/paw) was marginally effective. Tyr8-BK, but not DABK, also caused a dose-related increase in mouse paw edema, with an EC50 of 1.3 nmol/paw. The response to Tyr8-BK (10 nmol/paw) in rat paw edema was antagonized by B2 receptor antagonists (HOE-140 or NPC 17731, 30 nmol/paw) but not by the B1 antagonist des-Arg9[Leu8]BK (DALBK, 100 nmol/paw). Daily intraplantar injections of Tyr8-BK (10 nmol/paw) for 7 days caused progressive desensitization (D) of edema in sham-operated and adrenalectomized Wistar rats. DABK (100 nmol/paw) caused marked paw edema in D paws from both groups, which was inhibited by DALBK (100 nmol/paw) and by dexamethasone (0.5mg/kg, s.c.). Systemic injection of lipopolysaccharide (10 micrograms/mouse, 24 h prior) potentiated the first and second phases of Formalin-induced pain but had no effect on paw edema. Coinjection of DABK (2-22 nmol/paw) with low doses of Formalin in lipopolysaccharide-treated mice, which had no effect on naive animals, dose dependently potentiated both phases of Formalin-induced pain but did not modify paw edema. These effects were antagonized by DALBK with ID50 values of 21.9 (first phase) and 64.1 (second phase) nmol/paw. Thus, both progressive desensitization of B2 receptors and systemic treatment with lipopolysaccharide induce a glucocorticoid-sensitive upregulation of B1 receptors mediating paw edema in the rat and Formalin-induced nociception in mice. These results suggest that induction of upregulation of B1 receptors may play important roles in controlling inflammatory processes and hyperalgesia.
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PMID:Expression of B1 kinin receptors mediating paw edema and formalin-induced nociception. Modulation by glucocorticoids. 884 14


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