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1.
l. a. houghton f. cremonini † m. camilleri † i. busciglio † c. fell v. cox d. h. alpers ‡ o. e. dewit § g. e. dukes § e. gray § r. lea a. r. zinsmeister ¶ & p. j. whorwell 《Neurogastroenterology and motility》2007,19(9):732-743
Visceral hypersensitivity is important in the pathophysiology of irritable bowel syndrome and thus a target for modulation in drug development. Neurokinin (NK) receptors, including NK(3) receptors, are expressed in the motor and sensory systems of the digestive tract. The aim of this study was to compare the effects of two different doses (25 and 100 mg) of the NK(3) receptor antagonist, talnetant (SB223412) with placebo on rectal sensory function and compliance in healthy volunteers studied at two centres. Rectal barostat tests were performed on 102 healthy volunteers, randomized to receive either oral talnetant 25 or 100 mg or placebo over 14-17 days. Studies were performed on three occasions: day 1 immediately prior to 1st dose, day 1 4 h postdose, and after 14- to17-day therapy. Compliance, and pressure thresholds for first sensation, urgency, discomfort and pain were measured using ascending method of limits, and sensory intensity ratings for gas, urgency, discomfort and pain determined during four random phasic distensions (12, 24, 36 and 48 mmHg). Talnetant had no effect on rectal compliance, sensory thresholds or intensity ratings compared with placebo. In general, the results obtained at the two centres differed minimally, with intensity scores at one centre consistently somewhat lower. At the doses tested, talnetant has no effect on rectal compliance or distension-induced rectal sensation in healthy participants. 相似文献
2.
The neurohormonal control of the migrating motor complex (MMC) is not fully understood. The hypothesis of the present study was that neuropeptide levels might vary with the different phases of the MMC and that a similar variation might be found in the secretions of the gastrointestinal tract. Thus, plasma and intraduodenal concentrations of vasoactive intestinal peptide (VIP), somatostatin (SOM), substance P (SP) and neurokinin A (NKA) were determined by radioimmunoassay every 10 min during two complete MMC cycles in eight male subjects. For comparison, plasma motilin (MOT) concentrations were measured. Plasma concentrations of MOT (mean peak value ± SEM; 39 ± 6 pmol L?1), but none of the neuropeptides studied, showed a cyclic variation in plasma with the different phases of the MMC. Peak intraduodenal concentrations of VIP (79 ± 23 pmol L?1),?SOM (2437 ± 432 pmol L?1) and SP (718 ± 326 pmol L?1) occurred at or at the time point before the onset of phase III of the MMC. No such correlation was observed for NKA. These results demonstrate that intraduodenal but not plasma concentrations of the neuropeptides VIP, SOM and SP show an association with phase III of the MMC. The biological relevance of this finding is yet unclear, but the results raise the possibility that gut neuropeptides may regulate fasting motility through a luminal release. 相似文献
3.
本文应用放射免疫分析方法,测定了16只哮喘豚鼠初级传入系统和中枢内神经激肽β(NKB)的水平。结果表明,与正常对照组(结状神经书3228±11.89,C7~C8段脊神经节23.63±13.26,T1~T2段脊神经节24.25±1819,T3~T5段脊神经节25.53±12.34,C7~T5段脊髓后角28.65±16.59,孤束核26.34±18.36Pg/gwettissue)相比较,哮喘豚鼠初级传入系统和中枢内(结状神经节43.26±12.35,C7~C段脊神经节32.53±17.63,T1~T2段神经书32.25±20.65,T3~T5段脊神经节34.36±15.33,C7~T5段脊髓后角39.53±2028,孤束核3662±17.85Pg/gwettissue)NKB的含量明显高于对照组(P<0.05)。结合NKB在呼吸道的作用,这些结果提示,初级传入系统和中枢内的NKB可能参与哮喘发病的病理生理机制。 相似文献
4.
探讨神经激肽A(NKA)在大鼠结肠发育中的表达及变化,应用免疫组织化学PAP法和图像分析系统观测大鼠胚胎13d至成年结肠中NKA的表达情况。结果显示:(1)在结肠,首先于胚胎17 d的肌间丛及上皮处出现NKA-IR的表达,随发育相继出现于纵肌、环肌、粘膜肌、固有膜、粘膜下层和粘膜丛,30 d时具备成年分布特征;(2)定量分析的结果与NKA~IR在结肠各层的变化一致;(3)NKA-IR细胞具有典型的肠道内分泌细胞的形态特征和分布特征。结果提示:(1)NKA在结肠的发生发育主要在生前5 d~生后4周内;(2)NKA在结肠的发生发育有两个关键时期,即生前5 d~生后1周和生后1月末;(3)NKA-IR细胞可能是肠道内分泌NKA的内分泌细胞;(4)NKA可能对大鼠结肠的发育具有重要作用,可能与结肠功能的建立密切相关。 相似文献
5.
M. RAHMAN M. L
RDAL A. AL-SAFFAR P. M. HELLSTR
M 《Acta physiologica (Oxford, England)》1994,151(4):497-505
We have studied the effect of a novel tachykinin, neuropeptide γ(NPγ) on small intestinal motility in the rat. Experiments were done in vitro on longitudinal muscle strips of duodenum, and in vivo on the migrating myoelectric complex (MMC) of the small intestine. In vitro, contractile effects of NPγ were compared with those of a selective neurokinin 1 (NK1) receptor agonist, substance P methyl ester (SPME), and a selective neurokinin 2 (NK2) receptor agonist, Nle10-NKA(4–10)(NleNKA). NPγ, SPME and NleNKA caused concentration-dependent contractions (P < 0.001). NPγ was eight-fold more potent than NleNKA, and 118-fold more potent than SPME. Contractile responses to NPγ were reduced by hexamethonium (P < 0.01) and atropine (P < 0.05). The non-selective NK receptor antagonist spantide I only slightly reduced the contractile response to NPγ, as did the selective NK1 antagonist GR 82334, and the selective NK2 antagonist L-659877 and MEN 10376. In vivo, effects of NPγ on the MMC were compared with those of the natural tachykinins substance P (SP) and neurokinin A (NKA). NPy disrupted the MMC and induced irregular spiking in a dose-dependent manner from 25 to 100 pmol kg-1 min-1 i.v. (P < 0.05). The effect of NPγ was more prominent than that of NKA at equal doses, while SP had no effect. Our findings show that NPγ exerts potent stimulatory effects on small intestinal motility, most likely mediated directly via distinct NK receptors on smooth muscle cells, but also indirectly via a cholinergic link. 相似文献
6.
大鼠消化道神经激肽A的发育研究 总被引:3,自引:1,他引:3
应用免疫细胞化学PAP法系统研究了大鼠胚胎13天至成年食道及胃神经激肽A发生发育过程。结果如下:(1)在食道,直至出生前,即胚胎21天才于环肌层及粘膜肌层出现阳性膨体纤维,出生后,随幼鼠的生长发育相继在上皮内、纵肌层、肌间丛、粘膜下丛出现神经激肽A免疫反应阳性物,其纤维的密度、粗细和着色也逐渐增加,30天时已具备成年的分布特征,其发育主要在生后4周;(2)在胃,于胚胎14天,首先在肌间丛处呈现阳性 相似文献
7.
神经激肽A免疫反应在哮喘豚鼠脊髓中的定量分析 总被引:1,自引:0,他引:1
用免疫细胞化学ABC法结合显微图像定量分析,研究了神经激肽A(NKA)免疫反应物在哮喘豚鼠脊髓中的分布及其变化。结果表明,NKA免疫反应纤维及终末分布于豚鼠C7~T5段脊髓后角Ⅰ~Ⅲ层和背外侧索核区,NKA样阳性免疫反应物的平均密度在前者为42.2%,后者为37.2%;它们的平均灰度值分别为134.7和92.9,与对照组(平均密度分别为27.2%和24.9%,平均灰度值分别为199.9和129.2)比较均有显著性差别(P<0.01)。这些研究结果提示脊髓内NKA可能参与了哮喘发作的神经病理生理机制,是其发作的重要因素之一。 相似文献
8.
Y.-P. LOU A. FRANCO-CERECEDA J. M. LUNDBERG 《Acta physiologica (Oxford, England)》1992,146(1):119-127
Vagal nerve stimulation (1 Hz for 1 min), capsaicin (10-8 M and 10-6 M), resiniferatoxin (3 × 10-10 M) and nicotine (10-4 M) evoked a non-cholinergic bronchoconstriction in the isolated perfused guinea-pig lung preparation. Simultaneously there was an increase in the perfusate levels of calcitonin gene-related peptide-like immunoreactivity, suggesting release from sensory nerves. Both the bronchoconstriction and peptide release evoked by a low concentration of capsaicin (10-8 M) and that evoked by nerve stimulation were depressed by tetrodotoxin, suggesting involvement of Na+ channel dependent depolarization. Since the effects of capsaicin (10-8 M) and vagal nerve stimulation were inhibited by ω-conotoxin but not influenced by nifedipine, the Ca2+-channel involved is probably of N-type. Furthermore, the capsaicin analogue resiniferatoxin also evoked ω-conotoxin sensitive peptide release and bronchoconstriction. At the higher capsaicin concentration (10-6 M), the functional response was only slightly inhibited by wconotoxin or tetrodotoxin indicating that capsaicin at this concentration evoked peptide release and functional effects through other mechanisms, probably involving Ca2+ fluxes in the non-selective cation channel associated with the proposed capsaicin receptor. The nicotine (10-4 M) evoked peptide release and bronchoconstriction were only marginally influenced by ω-conotoxin or tetrodotoxin. It is concluded that the ion-channel mechanisms underlying the peptide releasing properties of antidromic nerve stimulation and low concentrations of capsaicin are similar and depend on action potential propagation, whereas capsaicin in high, toxic concentration and nicotine mainly act via receptor operated channels. 相似文献
9.
Our goal was to test the following hypotheses: 1) GABAA receptors facilitate neurokinin release from primary afferent terminals; 2) they do this by suppressing an inhibitory effect of GABAB receptors; 3) the activation of these two receptors is controlled by the firing frequency of primary afferents. We evoked neurokinin release by stimulating the dorsal root attached to spinal cord slices, and measured it using neurokinin 1 receptor (NK1R) internalization. Internalization evoked by root stimulation at 1 Hz (but not at 100 Hz) was increased by the GABAA receptor agonists muscimol (effective concentration of drug for 50% of the increase [EC50] 3 μM) and isoguvacine (EC50 4.5 μM). Internalization evoked by root stimulation at 100 Hz was inhibited by the GABAA receptor antagonists bicuculline (effective concentration of drug for 50% of the inhibition [IC50] 2 μM) and picrotoxin (IC50 243 nM). Internalization evoked by incubating the root with capsaicin (to selectively recruit nociceptive fibers) was increased by isoguvacine and abolished by picrotoxin. Therefore, GABAA receptors facilitate neurokinin release. Isoguvacine-facilitated neurokinin release was inhibited by picrotoxin, low Cl−, low Ca2+, Ca2+ channel blockers and N-methyl-d-aspartate receptor antagonists. Bumetanide, an inhibitor of the Na+-K+-2Cl− cotransporter, inhibited isoguvacine-facilitated neurokinin release, but this could be attributed to a direct inhibition of GABAA receptors. The GABAB agonist baclofen inhibited NK1R internalization evoked by 100 Hz root stimulation (IC50 1.5 μM), whereas the GABAB receptor antagonist (2S)-3-[[(1S)-1-(3,4-dichlorophenyl)ethyl]amino-2-hydroxypropyl](phenylmethyl) phosphinic acid (CGP-55845) increased NK1R internalization evoked by 1 Hz root stimulation (EC50 21 nM). Importantly, baclofen inhibited isoguvacine-facilitated neurokinin release, and CGP-55845 reversed the inhibition of neurokinin release by bicuculline. In conclusion, 1) GABAB receptors located presynaptically in primary afferent terminals inhibit neurokinin release; 2) GABAA receptors located in GABAergic interneurons facilitate neurokinin release by suppressing GABA release onto these GABAB receptors; 3) high frequency firing of C-fibers stimulates neurokinin release by activating GABAA receptors and inhibiting GABAB receptors, whereas low frequency firing inhibits neurokinin release by the converse mechanisms. 相似文献
10.
- Following induction of acute inflammation by intraarticular injection of kaolin and carrageenan into the knee joint in rats, there was a significant decrease in the withdrawal latency to radiant heat applied to the paw (i.e. heat hyperalgesia), an increased joint circumference and increased joint temperature.
- A neurokinin1 (NK1) receptor antagonist (CP-99,994, 10 mM) had no effect on the paw withdrawal latency when it was administered spinally through a microdialysis fibre before the induction of inflammation. Pretreatment with a NK2 receptor antagonist (SR48968, 1 mM) administered spinally through the microdialysis fibre prevented the heat hyperalgesia from developing in the early stages of the inflammation.
- Post-treatment through the microdialysis fibre with the NK1 receptor antagonist (0.0110 mM) was effective in reversing the heat hyperalgesia. In contrast, post-treatment spinally with the NK2 receptor antagonist (0.011 mM) had no effect on the heat hyperalgesia. The inactive stereoisomers of the NK1 receptor antagonist, CP100,263, or the NK2 receptor antagonist, SR48965, administered at the same doses, had no effect on the joint inflammation or the heat hyperalgesia.
- Pretreatment systemically with the NK1 receptor antagonist (30 mg kg−1) had no effect on the heat hyperalgesia or pain-related behaviour ratings where 0 is none and 5 is non weight bearing and complete avoidance of limb contact. Pretreatment with a NK2 receptor antagonist (10 mg kg−1) systemically prevented the heat hyperalgesia and pain-related behaviour ratings from developing in the early stages of the inflammation. The inactive stereoisomers of NK1 receptor antagonist, CP100,263, or the NK2 receptor antagonist, SR48965, administered at the same doses, had no effect on the joint inflammation or the heat hyperalgesia.
- Post-treatment systemically with either the NK1 (0.130 mg kg−1) or the NK2 (0.110 mg kg−1) receptor antagonist resulted in a dose-dependent reversal of the heat hyperalgesia. Pain-related behaviour ratings were reduced by post-treatment only with the NK1 receptor antagonist. The inactive stereoisomers of the NK1 receptor antagonist, CP100,263, or the NK2 receptor antagonist, SR48965, administered at the same doses, had no effect on the behavioural responses.
- Direct pretreatment of the knee joint with either the NK1 (30 mg) or the NK2 (10 mg) receptor antagonist prevented the heat hyperalgesia from developing without affecting joint swelling. The inactive stereoisomers of the NK1 receptor antagonist, CP100,263, or the NK2 receptor antagonist, SR48965, administered at the same doses, had no effect on the joint inflammation or the heat hyperalgesia.
- There appears to be a differential role for the spinal tachykinin receptors in the development and maintenance of the heat hyperalgesia associated with acute joint inflammation. The NK2 receptors appear to be activated early in the development of the heat hyperalgesia and NK1 receptors are involved in the maintenance of the heat hyperalgesia.
- Peripherally, both NK1 and NK2 receptors are involved in the development of heat hyperalgesia and pain-related behaviour ratings induced by acute inflammation.