Bartho L, Holzer P
Department of Pharmacology, University Medical School Pecs, Hungary.
Naunyn Schmiedebergs Arch Pharmacol. 1995 Dec;353(1):102-9. doi: 10.1007/BF00168922.
The effect of capsaicin-induced stimulation of afferent neurons on peristalsis and the possible neural mediators involved in this action were examined in the guinea-pig isolated ileum. The intraluminal pressure threshold for eliciting peristaltic waves was used to quantify facilitation (decrease in threshold) or inhibition (increase in threshold) of peristalsis. Capsaicin (0.1-1 microM) caused an initial short-lasting stimulation of peristalsis followed by a prolonged inhibition of peristaltic activity. Capsaicin (1 microM) was ineffective when the gut segments had been pretreated with 3.3 microM capsaicin, which is indicative of an afferent neuron-dependent action of the drug. In contrast, the abolition of peristalsis caused by a high concentration of capsaicin (33 microM) was fully reversible on removal and reproducible on readministration of capsaicin, a feature characteristic of a nonspecific depression of smooth muscle excitability. Baseline peristalsis and the excitatory/inhibitory effect of capsaicin (1 microM) on peristalsis remained unaltered by a combination of the tachykinin NK1 receptor antagonist (+)-(2S, 3S)-3-(2-methoxybenzylamino)-2-phenyl piperidine (CP-99,994; 0.3 microM) and the tachykinin NK2 receptor antagonist (L(-)-N-methyl-N[4-acetylamino-4-phenyl-piperidine-2-(3,4- -dichlorophenyl)butyl]-benzamide (SR-48,968; 0.1 microM). Further experiments, performed in the presence of a low concentration of atropine (10 nM) showed that the calcitonin gene-related peptide (CGRP) antagonist human alpha-calcitonin gene-related peptide (8-37) [hCGRP(8-37); 10 microM] attenuated the delayed inhibitory effect of capsaicin on peristalsis, but did not influence baseline peristaltic activity and the capsaicin-induced facilitation of peristalsis. Blockade of nitric oxide (NO) synthesis by NG-nitro-L-arginine methylester (L-NAME, 300 microM) facilitated baseline peristaltic activity and reduced the delayed inhibition of peristalsis caused by capsaicin (1 microM) without affecting the initial peristalsis-stimulating action of capsaicin. The effects of L-NAME were prevented by L-arginine (1 mM). The data of the current study indicate that capsaicin-sensitive afferent neurons do not participate in the neural pathways subserving peristalsis in the guinea-pig small intestine, but modulate peristaltic activity upon stimulation with capsaicin. The initial stimulant action of capsaicin on peristalsis is independent of tachykinins acting via NK1 or NK2 receptors, while the delayed capsaicin-induced depression of peristalsis involves CGRP and NO.
在豚鼠离体回肠中，研究了辣椒素诱导的传入神经元刺激对蠕动的影响以及参与此作用的可能神经介质。引发蠕动波的腔内压力阈值用于量化蠕动的促进作用（阈值降低）或抑制作用（阈值升高）。辣椒素（0.1 - 1微摩尔）引起蠕动的初始短暂刺激，随后是蠕动活动的长期抑制。当肠段用3.3微摩尔辣椒素预处理后，1微摩尔辣椒素无效，这表明该药物的作用依赖于传入神经元。相反，高浓度辣椒素（33微摩尔）引起的蠕动消失在去除辣椒素后完全可逆，重新给予辣椒素时可重现，这是平滑肌兴奋性非特异性抑制的特征。速激肽NK1受体拮抗剂（+） - （2S，3S） - 3 - （2 - 甲氧基苄基氨基） - 2 - 苯基哌啶（CP - 99,994；0.3微摩尔）和速激肽NK2受体拮抗剂（L（ - ） - N - 甲基 - N[4 - 乙酰氨基 - 4 - 苯基 - 哌啶 - 2 - （3,4 - 二氯苯基）丁基] - 苯甲酰胺（SR - 48,968；0.1微摩尔）联合使用时，基线蠕动以及辣椒素（1微摩尔）对蠕动的兴奋/抑制作用保持不变。在低浓度阿托品（10纳摩尔）存在下进行的进一步实验表明，降钙素基因相关肽（CGRP）拮抗剂人α - 降钙素基因相关肽（8 - 37）[hCGRP（8 - 37）；10微摩尔]减弱了辣椒素对蠕动的延迟抑制作用，但不影响基线蠕动活动和辣椒素诱导的蠕动促进作用。NG - 硝基 - L - 精氨酸甲酯（L - NAME，300微摩尔）阻断一氧化氮（NO）合成可促进基线蠕动活动，并减少辣椒素（1微摩尔）引起的蠕动延迟抑制，而不影响辣椒素最初的蠕动刺激作用。L - 精氨酸（1毫摩尔）可阻止L - NAME的作用。本研究数据表明，辣椒素敏感的传入神经元不参与豚鼠小肠蠕动的神经通路，但在辣椒素刺激时调节蠕动活动。辣椒素对蠕动的初始刺激作用独立于通过NK1或NK2受体起作用的速激肽，而辣椒素诱导的蠕动延迟抑制涉及CGRP和NO。
