Ballet S, Aubel B, Mauborgne A, Poliénor H, Farré A, Cesselin F, Hamon M, Bourgoin A S
INSERM U288, NeuroPsychoPharmacologie Moléculaire, Cellulaire et Fonctionnelle, Faculté de Médecine Pitié-Salpêtrière, 91, Boulevard de l'Hôpital, 75634 Paris cedex 13, France.
Neuropharmacology. 2001 Mar;40(4):578-89. doi: 10.1016/s0028-3908(00)00186-6.
Although previous studies have established that cizolirtine (5-([(N,N-dimethylaminoethoxy)phenyl]methyl)-1-methyl-1H-pyrazol citrate) is a potent analgesic in rodents, its mechanism(s) of action remain(s) unclear. In vitro and in vivo approaches were used to assess whether cizolirtine could affect the spinal release of two pain-related neuropeptides, substance P (SP) and calcitonin gene-related peptide (CGRP), in rats. Cizolirtine significantly reduced the K(+)-evoked overflow of both the SP-like material (SPLM; -25% at 0.1 microM--0.1 mM) and CGRPLM (-20% at 0.1--1.0 microM) from slices of the dorsal half of the lumbar enlargement of the spinal cord. Intrathecal perfusion in halothane-anaesthetized rats showed that local application of cizolirtine markedly diminished the spinal outflow of SPLM (up to -50% at 0.1 mM) but only marginally that of CGRPLM. Systemic administration of cizolirtine at an analgesic dose (80 mg/kg i.p.) also reduced spinal SPLM outflow (-50%) but not that of CGRPLM. Under both in vitro and in vivo conditions, idazoxan (10 microM) antagonized the effects of cizolirtine on SPLM and CGRPLM release, suggesting their mediation through alpha(2) adrenoceptors.
尽管先前的研究已证实西佐利定（5-([(N,N-二甲基氨基乙氧基)苯基]甲基)-1-甲基-1H-吡唑柠檬酸盐）在啮齿动物中是一种强效镇痛药，但其作用机制仍不清楚。采用体外和体内方法评估西佐利定是否会影响大鼠脊髓中两种与疼痛相关的神经肽——P物质（SP）和降钙素基因相关肽（CGRP）的释放。西佐利定显著降低了脊髓腰膨大背侧半切片中K⁺诱发的SP样物质（SPLM；0.1微摩尔至0.1毫摩尔时降低25%）和CGRPLM（0.1至1.0微摩尔时降低20%）的溢出。在氟烷麻醉的大鼠中进行鞘内灌注表明，局部应用西佐利定可显著减少SPLM的脊髓流出量（0.1毫摩尔时高达-50%），但对CGRPLM的减少作用很小。以镇痛剂量（80毫克/千克腹腔注射）全身给药西佐利定也可减少脊髓SPLM流出量（-50%），但对CGRPLM无此作用。在体外和体内条件下，咪唑克生（10微摩尔）均拮抗西佐利定对SPLM和CGRPLM释放的作用，提示其通过α₂肾上腺素能受体介导。
