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 some diseases in which endothelin-1 production increases, e.g. prostate cancer, endothelin-1 is considered to be involved in the generation of pain. In the present study, we investigated the effects of a selective endothelin ET(A) receptor antagonist, (E)-N-[6-methoxy-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl]-2-phenylethenesulfonamide monopotassium salt (YM598), on the nociception potentiated by endothelin-1 in a cancer inoculation-induced pain model in mice, induced by inoculation of the androgen-independent human prostate cancer cell line PPC-1 into the hind paws of severe combined immunodeficiency (SCID) mice. No pain responses were observed in the sham-operated mice, whereas monophasic pain responses were observed in the PPC-1-inoculated mice. Endothelin-1 (1 to 10 pmol/paw) but not sarafotoxin S6c potentiated the pain response in prostate cancer-inoculated mice. Both YM598 and atrasentan (0.3 to 3 mg/kg, p.o.) significantly inhibited the endothelin-1 (10 pmol/paw)-induced potentiation of nociception in a dose-dependent manner. These results suggest that selective endothelin ET(A) receptor antagonists might relieve pain in patients with various diseases in which endothelin-1 production is increased, e.g. prostate cancer.
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PMID:Effects of selective endothelin ET(A) receptor antagonists on endothelin-1-induced potentiation of cancer pain. 1517 62

Tumors including sarcomas and breast, prostate, and lung carcinomas frequently grow in or metastasize to the skeleton where they can induce significant bone remodeling and cancer pain. To define products that are released from tumors that are involved in the generation and maintenance of bone cancer pain, we focus here on endothelin-1 (ET-1) and endothelin receptors as several tumors including human prostate and breast have been shown to express high levels of ETs and the application of ETs to peripheral nerves can induce pain. Here we show that in a murine osteolytic 2472 sarcoma model of bone cancer pain, the 2472 sarcoma cells express high levels of ET-1, but express low or undetectable levels of endothelin A (ETAR) or B (ETBR) receptors whereas a subpopulation of sensory neurons express the ETAR and non-myelinating Schwann cells express the ETBR. Acute (10 mg/kg, i.p.) or chronic (10 mg/kg/day, p.o.) administration of the ETAR selective antagonist ABT-627 significantly attenuated ongoing and movement-evoked bone cancer pain and chronic administration of ABT-627 reduced several neurochemical indices of peripheral and central sensitization without influencing tumor growth or bone destruction. In contrast, acute treatment (30 mg/kg, i.p.) with the ETBR selective antagonist, A-192621 increased several measures of ongoing and movement evoked pain. As tumor expression and release of ET-1 has been shown to be regulated by the local environment, location specific expression and release of ET-1 by tumor cells may provide insight into the mechanisms that underlie the heterogeneity of bone cancer pain that is frequently observed in humans with multiple skeletal metastases.
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PMID:Endothelin and the tumorigenic component of bone cancer pain. 1520 37

In some diseases in which endothelin-1 (ET-1) production increases (e.g. prostate cancer), ET-1 is considered to be involved in the generation of pain. In the present study, we investigated the effects of a selective endothelin-A receptor antagonist, YM598, on the nociception potentiated by ET-1 in formalin-induced and cancer inoculation-induced pain models in mice. The formalin-induced pain model was prepared by intraplantar injection of 0.7% formalin into the hind paws of ICR mice, and the cancer pain model was prepared by inoculation of the human prostate cancer cell line PPC-1 into the hind paws of severe combined immunodeficiency mice. Formalin caused a biphasic pain response and paw edema in the mouse hind paw. ET-1 (10 pmol/paw) potentiated these responses, and single oral administration of YM598 (0.3-3 mg/kg) significantly inhibited this ET-1-induced potentiation of nociception and paw edema. ET-1 (10 pmol/paw) also potentiated the pain response in prostate cancer-inoculated mice. Both YM598 and atrasentan (0.3-3 mg/kg) significantly inhibited the ET-1-induced potentiation of nociception. These results suggest that selective endothelin-A receptor antagonists relieve pain in patients with various diseases in which ET-1 production increases (e.g. prostate cancer).
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PMID:Inhibitory effects of a selective endothelin-A receptor antagonist YM598 on endothelin-1-induced potentiation of nociception in formalin-induced and prostate cancer-induced pain models in mice. 1583 53

Peripheral vascular disease can compromise the blood supply to the lower limb with amputation being necessary in severe cases. Reduced blood flow may be due to arterial occlusive disease or constriction of skeletal microvessels with the resultant ischaemia causing pain, tissue damage, ulceration and gangrene. These events are associated with endothelial damage or dysfunction: endothelin-1 is implicated as a mediator via its constrictor, proinflammatory and proliferative actions. Raised plasma and tissue levels of this peptide have been described in various ischaemic conditions, including peripheral vascular disease. Here, the possible role of endothelin-1 in peripheral vascular disease is discussed and potential therapeutic tools are considered.
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PMID:A role for endothelin-1 in peripheral vascular disease. 1624 75

Increasing evidence indicates that endothelin-1 has a role for peripheral nociceptive signaling in animals and humans. However, the mechanisms of the nociceptive effects of endothelin-1 have not been fully understood. The current study investigated the effects of endothelin-1 on the capsaicin-evoked intracellular Ca2+ response of cultured adult mice dorsal root ganglion neurons. Dorsal root ganglia were harvested from adult male C57B6N mice and were cultured. With a digital image analysis system, we detected the [Ca2+]i image of cultured dorsal root ganglion cells after loading with Fura-2 acetoxymethyl. In addition, co-localization of protein kinase Cepsilon with transient receptor potential V1 and the translocation of protein kinase Cepsilon were investigated using immunohistochemical methods. Endothelin-1 (10 nM) enhanced an increase in [Ca2+]i by capsaicin (10 nM) from 87.6+/-11.6 nM to 414.8+/-62.3 nM (71 of 156 neurons). The inhibition of endothelin A receptor (BQ-123) significantly suppressed the enhancing effect of endothelin-1. In addition, a nonselective protein kinase C inhibitor (bisindolylmaleimide I) significantly suppressed the enhancing effect of endothelin-1. A myristoyl-tagged membrane-permeant-protein kinase Cepsilon V1-2 inhibitory peptide also significantly suppressed the enhancing effect of endothelin-1. In the immunocytochemical study, protein kinase Cepsilon immunoreactivity was found in most of transient receptor potential V1-positive neurons. After endothelin-1 application, protein kinase Cepsilon immunoreactivity was observed to be translocated from the cytosol to the cell membrane in transient receptor potential V1-positive neurons. Our results indicate that endothelin-1 enhances the response of dorsal root ganglion neurons to capsaicin in a protein kinase Cepsilon-dependent manner. Our findings may lead to a new strategy to treat pain associated with endothelin-1.
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PMID:Endothelin-1 enhances capsaicin-evoked intracellular Ca2+ response via activation of endothelin a receptor in a protein kinase Cepsilon-dependent manner in dorsal root ganglion neurons. 1629 80

A locally accelerated bone turnover is the pathophysiological basis of Paget's disease of bone (PD) and may result in severe bone deformations and pain. Affected bone sites are hypervascularized. Secreted endothelial products such as endothelin-1 (ET-1), influence bone metabolism. We investigated a possible correlation between ET-1 plasma concentrations and bone metabolism in patients with PD and whether ET-1 plasma levels are regulated by i. v. bisphosphonate treatment. Plasma ET-1 levels were determined in 22 patients with PD and found to be significantly (p = 0.006) elevated (0.75 +/- 0.48 fmol/ml) compared to 19 healthy controls (0.20 +/- 0.24 fmol/ml). In a group of five patients with PD, plasma ET-1 levels were determined before and after treatment with i. v. pamidronate. On the average, ET-1 levels decreased by 21 % after pamidronate infusions (p = 0.045). The results suggest that bone metabolism in pagetic bone affects endothelial cell metabolism and may also be modulated by endothelial cell products. ET-1 plasma levels may indicate PD activity.
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PMID:Endothelin-1 levels in patients with Paget's disease of bone. 1632 Jan 59

Subcutaneous endothelin-1 (ET-1; 200 microM, 2 nmoles/paw) injected into the rat hind paw, has been shown to cause robust hind paw flinching (HPF) and paw licking, and to induce impulses selectively in primary nociceptors. Here we report that a much lower [ET-1] sensitizes the paw to a nocifensive withdrawal response to tactile stimulation (by von Frey hairs, VFH), a sensitization that involves local TRPV1 receptors. Injection of 10 microM ET-1 (0.1 nmole/paw) causes only marginal HPF but rapidly (20 mins after injection) lowers the force threshold for paw withdrawal (PWT) to VFH, to approximately 30% of pre-injection baseline. Such tactile allodynia persists for 3 hrs. In rats pre-injected with the TRPV1-antagonists capsazepine (CPZ; 1.33 mM) or 5'-iodoresiniferatoxin (I-RTX; 0.13 microM), 15 min before ET-1, a fast initial drop in PWT, as with ET-1 alone, occurs (to 40% or to 19% of baseline, respectively), but this earliest reduction then regresses back to the pre-injection PWT value more rapidly than with ET-1 alone. The recovery of allodynia from the maximum value is about two times faster for ET-1+CPZ and about 4 times faster for ET-1+ I-RTX, compared with that from ET-1 +vehicle (t(1/2) = 130, 60, and 250 mins, respectively). In contrast, spontaneous pain indicated by overt HPF from ET-1 is not attenuated by TRPV1 antagonists. Tactile allodynia is similarly abbreviated by antagonists of both ET(A) (BQ-123, 32 nmoles/paw) and ET(B) (BQ-788, 30 nmoles/paw) receptors, whereas HPF is abolished by this ET(A) antagonist but enhanced by the ET(B) antagonist. We conclude that low ET-1 causes tactile allodynia, which is characterized by a different time-course and pharmacology than ET-1-induced nociception, and that local TRPV1 receptors are involved in the maintenance of this ET-1-induced allodynia but not in the overt algesic action of ET-1.
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PMID:Tactile allodynia initiated by local subcutaneous endothelin-1 is prolonged by activation of TRPV-1 receptors. 1674 Oct 70

In this study we investigated the role of endothelin-1 (ET-1) and its peripheral receptor (ET-A) in carcinoma-induced pain in a mouse cancer pain model. Tumors were induced in the hind paw of female mice by local injection of cells derived from a human oral squamous cell carcinoma (SCC). Significant pain, as indicated by reduction in withdrawal thresholds in response to mechanical stimulation, began at four days after SCC inoculation and lasted to 28 days, the last day of measurement. Intra-tumor expression of both ET-1 mRNA and ET-1 protein were significantly upregulated compared to normal tissue, and local administration of the ET-A receptor selective antagonist, BQ-123 (100 microM) significantly elevated withdrawal thresholds, indicating the induction of an antinociceptive effect. These findings support the suggestion that ET-1 and ET-A receptors contribute to the severity of carcinoma-induced soft tissue cancer pain.
Eur J Pain 2007 May
PMID:Peripheral endothelin A receptor antagonism attenuates carcinoma-induced pain. 1680 13

Although pain is a frequent feature in patients with cancer, its etiology is still poorly understood. In recent years, endothelin-1 (ET-1) has become a major target molecule in the etiology of cancer pain. In this randomised, double-blind study the effects of intradermal injection of ET-1 on spontaneous pain, temperature perception and sensation of punctate stimulation were evaluated. Thirty-five subjects were randomised to receive either placebo or one of four concentrations of ET-1 (ranging from 10(-10) to 10(-6)M). Besides assessment of spontaneous pain, three neurosensory testings were performed: (1) cold and warm sensation, (2) cold and heat pain, and (3) punctate stimulation using a von Frey monofilament. ET-1 produced a dose-dependent flare zone that was absent after placebo injection. Subjects reported a short-lasting spontaneous pain upon administration of the highest concentrations of ET-1. Injection of ET-1 induced a long-lasting and dose-dependent punctate hyperalgesia in an area around the injection site (secondary hyperalgesia). Thermal testing revealed a short period of hypoesthesia to non-noxious warm and cold stimuli after some doses of ET-1. In addition to the mechanical hyperalgesia, intradermal injection of ET-1 almost instantaneously induced a state of cold hyperalgesia outlasting the study period (120 min). No development of heat hyperalgesia was observed. The observed psychophysical characteristics of this new model of ET-1 induced nociception indicate its potential as a human experimental model for cancer pain.
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PMID:Neurosensory changes in a human model of endothelin-1 induced pain: a behavioral study. 1740 78

The contribution of endothelin-1 (ET-1), acting via endothelin-A receptors (ET(A)), on post-incisional pain was examined in a rat model of incision through the hairy skin of the lumbar dorsum. Post-incisional mechanical hyperesthesia was evaluated by cutaneous trunci muscle reflexes (CTMR) of subcutaneous muscles responding to stimulation with von Frey filaments near the wound (primary responses) and at a distance, especially on the contralateral dorsum (secondary responses, involving spinal circuits). The role of ET(A) was determined by pre-incisional, subcutaneous injection of the selective receptor antagonist BQ-123 at the incision site, 15 min or 24h before surgery. Control incisions showed both primary tactile allodynia and hyperalgesia, and a weaker secondary hyperesthesia, peaking 3-4h after surgery and lasting at least 24h. Primary allodynia, but not hyperalgesia, was dose-dependently suppressed by 15 min pre-incisional BQ-123. In contrast, both secondary allodynia and hyperalgesia were inhibited by local BQ-123. The suppression of primary allodynia by local antagonist disappeared in 24h, but that of secondary hyperesthesia remained strong for at least 24h. Systemically delivered BQ-123 was without effect on any post-incisional hyperesthesia, and if the antagonist was locally injected 24h before surgery there was no difference on hyperesthesia compared to vehicle injected at that time. We conclude that ET-1, released from skin by incision, activates nociceptors to cause primary allodynia and to sensitize spinal circuits through central sensitization. Blockade of ET(A) in the immediate peri-operative period prevents the later development of central sensitization.
Pain 2007 Dec 15
PMID:Cutaneous endothelin-A receptors elevate post-incisional pain. 1746 72


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