Culman J, Klee S, Ohlendorf C, Unger T
Department of Phamacology, Christian-Albrechts-University of Kiel, Germany.
J Pharmacol Exp Ther. 1997 Jan;280(1):238-46.
The neurokinins, substance P (SP) and neurokinin A (NKA) represent natural, nonspecific ligands of NK1 and NK2 receptors. In our study in conscious rats, we tested the hypothesis that neurokinins, especially SP, are used by neuronal circuits to generate cardiovascular and behavioral responses to stress by using the selective, high-affinity, nonpeptide antagonists of NK1 and NK2 receptors, CP-96, 345, RP 67580 and SR 48968, respectively, Formalin injected s.c. through a chronically implanted catheter in the region of the lower leg was used as a stress stimulus. The antagonists and their inactive enantiomers, RP 68651 and SR 48965, as a control for nonspecific activity, were injected intracerebroventricularly (i.c.v.) 10 min before the s.c. injection of formalin. Formalin (2.5%, 50 microliters, s.c.) induced a marked increase in mean arterial pressure (MAP) and heart rate (HR) as well as hind limb grooming/biting (HG) as the dominant behavioral manifestation. Pretreatment with the NK1 receptor antagonist, CP-96,345 (5 nmol, i.c.v.), significantly attenuated only the HR (-54%; P < .01) but not the MAP response to formalin. The NK1 receptor antagonist, RP 67580, injected i.c.v. at doses of 100, 500 and 2500 pmol significantly reduced both, the MAP and HR responses to formalin by maximally 63% (P < .01) and 52% (P < .01), respectively. In a separate set of experiments, we compared the effect of the individual and simultaneous blockade of central NK1 and NK2 receptors on the cardiovascular and behavioral responses to formalin stress. Pretreatment with RP 67580 (100 pmol, i.c.v.) attenuated the MAP (-30%; P < .05), HR (-40%; P < .01) and HG (P < .05) responses to formalin. The NK2 receptor antagonist, SR 48968 (650 pmol, i.c.v.), affected neither the cardiovascular nor the behavioral responses. i.c.v. pretreatment with both tachykinin receptor antagonists (RP 67580: 100 pmol; SR 48968: 650 pmol) reduced the MAP, HR and HG responses to formalin to the same extent as RP 67580 alone. Pretreatment with the inactive enantiomers, RP 68651 (100 pmol, i.c.v.) and SR 48965 (650 pmol, i.c.v.) did not alter the cardiovascular and behavioral responses to formalin. Our results demonstrate that centrally administered NK1 receptor antagonists inhibit the cardiovascular and behavioral reactions in response to a noxious stimulus. They provide first pharmacological evidence that endogenous SP acts as mediator of stress responses in the brain.
神经激肽、P物质（SP）和神经激肽A（NKA）是NK1和NK2受体的天然非特异性配体。在我们对清醒大鼠的研究中，我们通过分别使用NK1和NK2受体的选择性、高亲和力非肽拮抗剂CP-96、345、RP 67580和SR 48968，来检验神经激肽尤其是SP是否被神经回路用于产生对应激的心血管和行为反应这一假设。通过一根长期植入的导管在小腿区域皮下注射福尔马林作为应激刺激。拮抗剂及其无活性对映体RP 68651和SR 48965作为非特异性活性对照，在皮下注射福尔马林前10分钟经脑室注射（i.c.v.）。福尔马林（2.5%，50微升，皮下）引起平均动脉压（MAP）和心率（HR）显著升高，以及作为主要行为表现的后肢梳理/啃咬（HG）。用NK1受体拮抗剂CP-96、345（5纳摩尔，i.c.v.）预处理仅显著减弱了HR（-54%；P<.01），但未减弱对福尔马林的MAP反应。经脑室注射剂量为100、500和2500皮摩尔的NK1受体拮抗剂RP 67580分别使对福尔马林的MAP和HR反应最大程度降低63%（P<.01）和52%（P<.01）。在另一组实验中，我们比较了单独和同时阻断中枢NK1和NK2受体对福尔马林应激的心血管和行为反应的影响。用RP 67580（100皮摩尔，i.c.v.）预处理减弱了对福尔马林的MAP（-30%；P<.05）、HR（-4%；P<.01）和HG（P<.05）反应。NK2受体拮抗剂SR 48968（650皮摩尔，i.c.v.）对心血管和行为反应均无影响。用两种速激肽受体拮抗剂（RP 67580：100皮摩尔；SR 48968：650皮摩尔）经脑室预处理使对福尔马林的MAP、HR和HG反应降低到与单独使用RP 67580相同的程度。用无活性对映体RP 68651（100皮摩尔，i.c.v.）和SR 48965（650皮摩尔，i.c.v.）预处理未改变对福尔马林的心血管和行为反应。我们的数据表明，中枢给予NK1受体拮抗剂可抑制对有害刺激的心血管和行为反应。它们提供了首个药理学证据，即内源性SP在大脑中作为应激反应的介质发挥作用。
