Xu X J, Dalsgaard C J, Wiesenfeld-Hallin Z
Karolinska Institute, Department of Clinical Physiology, Huddinge University Hospital, Sweden.
Eur J Pharmacol. 1992 Jun 17;216(3):337-44. doi: 10.1016/0014-2999(92)90428-7.
We have examined the effects of intrathecally (i.t.) administered CP-96,345, a non-peptide NK1 receptor ligand, on the spinal nociceptive flexor reflex and on the facilitation of this reflex evoked by i.t. substance P (SP), neurokinin A (NKA) and electrical conditioning stimulation of cutaneous C-afferents. CP-96,345 i.t. at 24 pmol-2.4 nmol had no significant effect on flexor reflex excitability. At the highest dose tested (24 nmol), CP-96,345 caused a brief facilitation of the flexor reflex, which was similar to the effect of the vehicle used at this drug concentration. CP-96,345 did not depress the flexor reflex at any dose. In rats with chronically implanted i.t. catheters, CP-96,345 at 24 nmol caused neither motor impairment nor morphological damage to the spinal cord. Pretreatment with CP-96,345 dose dependently and similarly antagonized facilitation of the flexor reflex induced by 7 pmol i.t. SP or by a 20-s, 1-Hz conditioning stimulus train applied to cutaneous C-fibers in the sural nerve innervation area. The vehicle had no effect. The antagonistic effect of CP-96,345 on the SP- and C-fiber reflex facilitation induced by conditioning stimulation became maximal only 20-30 min after the i.t. injection and lasted 3-4 h at the highest dose. CP-96,345 did not significantly block the facilitatory effect of 7 pmol i.t. NKA on the flexor reflex. These results demonstrate that CP-96,345 is a potent, long-lasting and selective antagonist of SP in rat spinal cord. Furthermore, facilitation of the flexor reflex (central sensitization) induced by conditioning stimulation of cutaneous C-afferents is mediated by NK1 tachykinin receptors, but the NK1 receptor may not be involved in the transmission of the flexor reflex. CP-96,345 is thus useful in experimental studies of the role of SP in the central nervous system.
我们研究了鞘内注射（i.t.）非肽类NK1受体配体CP-96,345对脊髓伤害性屈肌反射以及对鞘内注射P物质（SP）、神经激肽A（NKA）和皮肤C类传入纤维电条件刺激所诱发的该反射易化作用的影响。鞘内注射24 pmol - 2.4 nmol的CP-96,345对屈肌反射兴奋性无显著影响。在测试的最高剂量（24 nmol）时，CP-96,345引起屈肌反射短暂易化，这与该药物浓度下所用溶媒的作用相似。CP-96,345在任何剂量下均未抑制屈肌反射。在长期植入鞘内导管的大鼠中，24 nmol的CP-96,345既未导致运动功能障碍，也未对脊髓造成形态学损伤。用CP-96,345预处理可剂量依赖性且相似地拮抗由鞘内注射7 pmol SP或对腓肠神经支配区域的皮肤C纤维施加20秒、1赫兹条件刺激序列所诱发的屈肌反射易化。溶媒无此作用。CP-96,345对条件刺激诱发的SP和C纤维反射易化的拮抗作用仅在鞘内注射后20 - 30分钟达到最大，并在最高剂量下持续3 - 4小时。CP-96,345未显著阻断鞘内注射7 pmol NKA对屈肌反射的易化作用。这些结果表明，CP-96,345是大鼠脊髓中SP的强效、长效且选择性拮抗剂。此外，皮肤C类传入纤维条件刺激所诱发的屈肌反射易化（中枢敏化）由NK1速激肽受体介导，但NK1受体可能不参与屈肌反射的传导。因此，CP-96,345在SP在中枢神经系统中作用的实验研究中很有用。
