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Query: UMLS:C0030193 (pain)
 261,466 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The impairment of endothelial function in hypercholesterolaemic animals and humans is known to be reversed by intravenous infusions of L-arginine (L-ARG), the precursor of NO. 22 patients with peripheral arterial obstructive disease (PAOD) received L-ARG (60 mmol) as intravenous infusions, each lasting three hours, daily for seven consecutive days. This treatment resulted in elongation of the painfree and maximum walking distances, as well as shortening of the period of time required for pain relief after walking the maximum distance. A rise in the ankle/arm pressure ratio (AAPR) was associated with an increase of arterial blood flow in both calves. The transcutaneous oxygen tension (tcpO2) in the ischaemic foot was also increased. After the 1st and the 7th infusion of L-ARG the spontaneous (PAR) as well as the ADP- and collagen-induced platelet aggregation were suppressed, the euglobulin clot lysis time (ECLT) shortened, plasma levels of platelet activator inhibitor (PAI) decreased, and cGMP levels increased. These data indicate beneficial effects of L-ARG as a therapeutic agent in patients with PAOD. We presume that in these patients high doses of exogenous L-ARG can be partially converted to NO.
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PMID:Treatment with L-arginine is likely to stimulate generation of nitric oxide in patients with peripheral arterial obstructive disease. 886 84

We have previously reported that we have observed chronic pain-like response to light mechanical stimuli (allodynia) in rats after severe spinal cord ischemia, which resembles some painful conditions in chronic spinally injured patients and is not relieved by a number of conventional analgesics used for treating chronic neuropathic pain. In the present study, we tested the effects of the non-selective nitric oxide synthase (NOS) inhibitor NG-nitro-L-arginine methyl ester (L-NAME) and the selective neuronal NOS inhibitor 7-nitro indazole (7-NI) and 6-nitro indazole (6-NI) on the chronic allodynia-like behavior. Systemic L-NAME dose-dependently relieved mechanical allodynia-like response in a stereo-specific and L-arginine-reversible manner without causing sedation or motor deficits. However, L-NAME significantly elevated systemic blood pressure. Systemic 7-NI relieved chronic allodynia in a L-arginine reversible manner, did not increase blood pressure or induce sedation, but caused motor deficits at a high dose, which was not reversed by L-arginine. Systemic 6-NI also relieved the chronic allodynia, which was however associated with severe sedation. In order to exclude the possibility that the effect of L-NAME on blood pressure was involved in the analgesic effect observed, the effect of systemically applied adrenaline was examined. Adrenaline increased the systemic blood pressure to a similar extent as L-NAME, but did not relieve allodynia. It is suggested that blockade of NOS by L-NAME relieved the chronic allodynia-like behavior in spinally injured rats. This effect was likely to be mediated by a blockade of neuronal isoforms of NOS, as 7-NI relieved the allodynia in a L-arginine-reversible manner. Consequently, generation of NO by neuronal NOS may be critically involved in the maintenance of this abnormal pain-related sensation. The possibility of using NOS inhibitors as potential novel analgesics is discussed.
Pain 1996 Aug
PMID:Treatment of a chronic allodynia-like response in spinally injured rats: effects of systemically administered nitric oxide synthase inhibitors. 888 Aug 55

Formalin injected subcutaneously into the hindpaw of the rat produces an animal model of inflammation that exhibits a phasic component and a tonic component of pain. We evaluated the effects of a nitric oxide synthase inhibitor, N omega-nitro-L-arginine methyl ester (L-NAME), on a formalin-induced behavior, hindpaw licking, and on Fos-labeling of nuclei in the fifth lumbar spinal segment. Our results demonstrated that pretreatment with intrathecal doses of 0.3 and 1.0 mg of L-NAME significantly reduced licking behavior associated with injection of formalin into the left hindpaw of the rat. In addition, these same doses of L-NAME reduced formalin-induced Fos-labeling in the ipsilateral dorsal gray matter (as compared to the contralateral gray matter). Qualitative assessment suggested that the reduction in labeling occurred primarily in the superficial dorsal horn. The stereoisomer, D-NAME, administered at the same doses had little to no effect on either formalin-induced licking or Fos-labeling. Finally, our results revealed that total licking time was related to Fos-labeling. Rats that spent less time licking the hindpaw exhibited a smaller increase in Fos-labeling. Our results suggest that the production of nitric oxide is associated with licking behavior resulting from formalin injection into the hindpaw of rats. Our results also suggest that the production of nitric oxide and Fos are associated. Indeed, these substances may be involved in spinal pathways associated with nociception.
Pain 1996 Aug
PMID:A nitric oxide synthesis inhibitor (L-NAME) reduces licking behavior and Fos-labeling in the spinal cord of rats during formalin-induced inflammation. 888 Aug 57

In a randomized, double-blind, double-dummy, single-dose, parallel-group study, oral ibuprofen arginine (400 mg) was compared with intramuscular (i.m.) morphine sulphate (5 or 10 mg) for post-operative pain relief after orthopaedic surgery in 120 patients. The study medication was administered post-operatively at the time when each patient first requested pain relief for moderate to severe pain. Assessment of pain intensity and pain relief was made using standard visual analogue scales and verbal rating scores. In all three groups, there was a reduction in pain compared with baseline, measured by visual analogue scales and verbal rating scores, at all time points up to completion of the study at 240 min. For example, visual analogue scales decreased by 35 (10-52) mm at 1 h in the morphine 5 mg group, 24 (12-39) mm in morphine 10 mg group and 21 (8-38) mm in the ibuprofen arginine group (median and inter-quartile range). Verbal rating scores showed a similar pattern. Comparing the groups over the whole study period using the sum of pain intensity differences showed no significant differences in pain experience between the groups. Assessment of total pain relief also showed no significant differences. The incidence and types of side effect seen were similar in the three groups.
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PMID:A comparison of ibuprofen arginine with morphine sulphate for pain relief after orthopaedic surgery. 888 25

Adherence of sickle erythrocytes to vascular endothelium likely initiates or participates in microvascular occlusion, leading to ischemic tissue and organ damage characteristic of sickle-cell pain episodes. In vitro, sickle-cell adherence to endothelium involves adhesive plasma proteins and integrin and nonintegrin receptors on sickle cells and endothelial cells. The involvement of arginine-glycine-aspartic acid (RGD) sequences in adhesive plasma proteins and integrin receptors suggests that RGD-containing peptides may inhibit sickle-cell/endothelial-cell adherence. In the present study, inhibition of plasma-mediated sickle-erythrocyte adherence to endothelium using conformationally constrained RGD-containing peptides was quantified in vitro under continuous flow at a shear stress of 1.0 dyn/cm2. Two conformationally constrained RGD peptides were investigated: 6Z (which has high affinity for alpha5beta1, alpha(V)beta3, and alpha(IIIb)beta3 integrin receptors), and TP9201 (which preferentially binds to alpha(IIb)beta3). Peptide 6Z at 50 microM inhibited plasma-mediated sickle-cell adherence to microvascular endothelium 70% when incubated with sickle red cells, and 63% when incubated with endothelium. Under similar conditions, peptide TP9201 inhibited plasma-mediated sickle-cell adherence up to 85% at concentrations from 250 to 500 microM TP9201. The inhibition of plasma-mediated adherence by conformationally constrained RGD peptides, but not by linear or circular constructs, suggests that the tertiary structure of the peptide containing the binding sequence is important. Inhibition of plasma-mediated sickle-cell adhesion with these peptides in vitro suggests that such conformationally constrained RGD peptides could provide therapeutic interventions in the course of the disease by inhibiting receptor-ligand interactions.
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PMID:Inhibition of plasma-mediated adherence of sickle erythrocytes to microvascular endothelium by conformationally constrained RGD-containing peptides. 889 33

The endogenous nonapeptide bradykinin is a powerful substance which activates nociceptors, resulting in the sensation of pain in man. We used a newly developed non-radioactive method to detect bradykinin binding sites in isolated dorsal root ganglion cells with gold-labelled bradykinin. In a subpopulation of cells, gold-labelled bradykinin was bound in different quantities. The proportion of somata with bradykinin binding markedly depended on the length of time in culture. After 0.75 days, bradykinin was bound to 43% of somata. This proportion increased to 85% after 1.75 days and then decreased to 27% after 5.75 days. Bradykinin was bound to cells of all sizes, ranging from 40 to 2000 microns2 with a maximum of 200-300 microns2. In some cells, binding was also seen along the processes. No correlation was found between the soma size and the density of bradykinin binding. Blocking the bradykinin binding at the B1 receptor with (Des-Arg10)-Lys-bradykinin and at the B2 receptor with D-Arg(Hyp3-Thi5.8-D-Phe7)-bradykinin, respectively, revealed that in 0.75-day-old cultures no or only a very small amount of B1 receptors are present. In 1.75-day-old cultures, the marked increase in the proportion of cells with positive bradykinin binding is due to a de novo expression of the B1 receptor subtype and an up-regulation of the B2 receptor subtype. The selective or combined addition of specific B1 and B2 receptor ligands revealed that both receptor subtypes are co-localized. These data show that cultured sensory neurons express not only B2, but during a short period of time in culture also B1 receptors. The data allow us to hypothesize that a transient increase in bradykinin receptor expression might be caused by cell injury due to disruption of the axon. The injury-induced up-regulation of the receptor in vivo could cause physiological reactions.
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PMID:Bradykinin receptors in cultured rat dorsal root ganglion cells: influence of length of time in culture. 893 54

Conditions such as hyperalgesia can occur days or months after the noxious insult. Substance P (SP) is released in response to noxious stimuli. Given the long-term effects of the N-terminus of SP on putative nociceptive transmitters, we investigated changes in formalin-induced nociception following an accumulation of SP N-terminal metabolites in mice. Pre-treatment with the N-terminal metabolite of SP, SP(1-7), was without effect when injected intrathecally (i.t.) 5 or 30 min before formalin. However, at 24 h, SP(1-7) increased behaviors during Phase 1, indicating hyperalgesia, and attenuated Phase 2 responses, consistent with antinociception. The nitric oxide (NO) synthase inhibitor, N omega-nitro-L-arginine methyl ester HCl (L-NAME), blocked both hyperalgesic and antinociceptive effects when co-injected with SP(1-7). Consistent with a NO-mediated pathway, L-arginine (L-arg), the N-terminal amino acid of SP and precursor to NO, mimicked the antinociceptive effect of SP(1-7) on Phase 2. The hyperalgesic effect of SP(1-7) in Phase 1, which was not mimicked by L-arg, was prevented by D-SP(1-7), a SP(1-7) antagonist. Thus, SP(1-7) modulates nociception via two distinct NO-mediated pathways. When injected for 7 days, tolerance developed to the antinociceptive effect of SP(1-7) on Phase 2, but not to the hyperalgesic effect on Phase 1. Intraperitoneally injected SP(1-7) also produced hyperalgesia during Phase 1, to which tolerance developed following seven daily injections. Together, these data support the hypothesis that an accumulation of SP N-terminal metabolites, either peripherally or within the spinal cord area, is sufficient for long-term modulation of multiple types of nociception with hyperalgesic responses being most persistent.
Pain 1996 Oct
PMID:Nitric oxide mediates long-term hyperalgesic and antinociceptive effects of the N-terminus of substance P in the formalin assay in mice. 895 39

1. The last decade has witnessed a phenomenal increase in our understanding of the pharmacology of bradykinin receptors, and has led to an appreciation of a key role for the peptide kinins as proinflammatory mediators. This short review summarises the major changes that have taken place in the expanding area of bradykinin receptor pharmacology, and highlights important advances that we hope to anticipate in the future. 2. Bradykinin receptors are cell surface, G-protein coupled receptors of the seven-transmembrane domained family. The existence of two subtypes of bradykinin receptor, B1 and B2, has been confirmed through the use of high affinity peptide and nonpeptide receptor antagonists, radioligand binding studies and, recently, receptor cloning and expression studies. 3. Differences in the affinities of B2 receptor antagonists, including those of the [D-Phe7]-bradykinin series, D-Arg-[Hyp3, Thi5, D-Tic7, Oic8]-bradykinin (Hoe140, Icatibant) and the non-peptide, WIN64338, have led to proposals of the possible existence of further subtypes of bradykinin receptor (including a tracheal B3 receptor), and/or of species homologues of the B2 receptor. 4. Molecular cloning techniques have identified the gene encoding B1 receptors in the rabbit, human and mouse, and B2 receptors in the rat, human and mouse. B1 and B2 receptor show little (36%) overall sequence homology. Cloning studies reveal the potential for the existence of species homologues of receptors. 5. The use of bradykinin receptor antagonists in vivo has led to an appreciation of the involvement of bradykinin receptors in inflammation. Evidence suggests a role for B2 receptors in more classical acute inflammatory events, such as oedema and inflammatory pain, whereas B1 receptors appear to be involved in chronic inflammatory responses, including certain forms of persistent hyperalgesia. 6. The continuing advances in our knowledge of the characteristics of bradykinin receptors through the further development of selective receptor antagonists and molecular biology techniques will aid in the rational design of drugs effective in the therapeutic manipulation of inflammatory processes and in the control of inflammatory disease.
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PMID:Bradykinin receptors. 911 69

Acute arthritis is associated with pain-related behavior, joint swelling and increased joint temperature. Arthritic animals exhibit a significant decrease in paw withdrawal latency 4, 5, 6, 7 and 8 h after induction of inflammation, when compared with baseline values, indicative of secondary hyperalgesia. Intra-articular injection of a non-specific nitric oxide synthase (NOS) inhibitor, NG-nitro-L-arginine methyl ester hydrochloride (L-NAME), resulted in a complete reversal of heat hyperalgesia and prevented further increase in joint swelling and temperature, while injection of either isotonic saline or the inactive enantiomer NG-nitro-D-arginine methyl ester (D-NAME) after induction of arthritis had no effect on any of these parameters. Intra-articular injection of 7-nitro-indazole (7-NINA), a selective neuronal NOS inhibitor, reversed the heat hyperalgesia for about 1 h but did not inhibit the increase in joint swelling or temperature. These results suggest an important role for nitric oxide (NO) in mediating peripheral nociceptive transmission and inflammation.
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PMID:Blockade of joint inflammation and secondary hyperalgesia by L-NAME, a nitric oxide synthase inhibitor. 914 Oct 60

The antinociception caused by the hydroalcoholic extract of Siphocampylus verticillatus (Campanulaceae) has been investigated in chemical and thermal models of nociception in mice. We have also assessed some of the mechanisms underlying the antinociceptive effect of the extract. The hydroalcoholic extract of S. verticillatus (60-1000 mg kg-1, i.p. or p.o.) produced dose-related, significant and long-lasting (6 to 8 h) inhibition of acetic acid-induced abdominal constriction in mice, with ID50 values of 204 and approximately 1000 mg kg-1, respectively. In the formalin test, the extract (100-1000 mg kg-1), given either intraperitoneally or orally, resulted in graded inhibition of both phases of formalin-induced pain, being about 2- to 4-fold more potent in attenuating the second phase of the pain. The calculated mean ID50 (mg kg-1) values for the earlier and the later phases were: 491 and 186 and 640 and 441, respectively. In addition, the extract (60-1000 mg kg-1, i.p. or p.o.) caused marked and dose-related inhibition of capsaicin-induced neurogenic pain with mean ID50 values of 420 and 485 mg kg-1, respectively. The hydroalcoholic extract, at the same doses, did not significantly affect the performance of animals in the rota-rod test, nor did it have any analgesic effect in the tail-flick or hot-plate tests. The treatment of animals with naloxone (5 mg kg-1, s.c.) significantly reversed the analgesic effect of both morphine (5 mg kg-1, s.c.) and the extract (300 mg kg-1, i.p.) when assessed against acetic acid-induced abdominal constrictions. The treatment of animals with L-arginine (600 mg kg-1, i.p.) significantly attenuated the antinociceptive effects of NG-nitro-L-arginine (L-NOARG) (75 mg kg-1, i.p.), of the hydroalcoholic extract (600 mg kg-1, i.p.) or of morphine (5 mg kg-1, s.c.), when analysed against the formalin test. In addition, adrenalectomy of animals 7 days before the tests significantly reversed the antinociception caused by the hydroalcoholic extract (300 mg kg-1, i.p.) in the formalin-induced pain. These data show that the hydroalcoholic extract of S. verticillatus has significant and long-lasting oral antinociception when assessed against both neurogenic and inflammatory models of nociception in mice. The precise mechanism responsible for the analgesic effect of the extract still remains unclear, but a great part of this effect seems to be partly related to an opioid-like action and involvement of the L-arginine-nitric oxide pathway. Finally, the antinociception caused by the hydroalcoholic extract of S. verticillatus is modulated by adrenal hormones.
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PMID:Mechanisms involved in the antinociceptive effect in mice of the hydroalcoholic extract of Siphocampylus verticillatus. 917 96


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