Bugajski J, Gadek-Michalska A, Bugajski A J
Department of Physiology, Institute of Pharmacology, Polish Academy of Sciences, Cracow.
J Physiol Pharmacol. 2002 Sep;53(3):453-62.
Acetylcholine potently stimulates the hypothalamic-pituitary-adrenal (HPA) axis. Cholinergic receptor agonist carbachol, given intraperitoneally (i.p.) or into the lateral cerebral ventricle (i.c.v.) to non-anesthetized rats acts via multiple pathways to stimulate the HPA axis. The present study sought to determine 1) the functional selectivity of carbachol for cholinergic muscarinic and/or nicotinic receptors involved in the stimulation of HPA axis; 2) the involvement of prostaglandins (PGs) generated by constitutive and inducible cyclooxygenase (COX-1 and COX-2) in the carbachol-induced ACTH and corticosterone secretion in non-stressed rats and animals exposed to social crowding stress for 7 days (24 per a cage for 6). Carbachol was given i.c.v. or i.p. and cholinergic receptor antagonists or cyclooxygenase isoenzyme antagonists were given by the same routes 15 min earlier. One hour after the last injection trunk blood was taken for ACTH and corticosterone determinations. Atropine (0.1 microg i.c.v.), a cholinergic receptor antagonist, totally abolished the carbachol (2 microg i.c.v.)-induced ACTH and corticosterone secretion and mecamylamine (20 microg i.c.v.), a selective nicotinic receptor antagonist, did not affect this secretion. This finding indicates that carbachol functions as a selective central cholinergic muscarinic receptor agonist for the HPA axis stimulation. Crowding stress significantly diminished the carbachol (0.2 mg/kg i.p.)-induced plasma ACTH and corticosterone levels measured 1 hr after administration. Pretreatment with indomethacin (2 mg/kg i.p.), a non-selective cyclooxygenase inhibitor, significantly diminished the ACTH and corticosterone responses to carbachol (0.2 mg/kg i.p.) in control rats and moderately decreased these responses in stressed rats. Piroxicam (0.2 and 2.0 mg/kg i.p.), a COX-1 inhibitor, considerably impaired the carbachol-induced ACTH and corticosterone responses in control rats and markedly diminished these responses in stressed rats. A selective COX-2 blocker, compound NS-398 (0.2 and 2.0 mg/kg i.p.), substantially decreased the carbachol-induced hormones secretion in control rats but did not markedly alter this secretion in stressed rats. These results indicate that in the carbachol-induced HPA axis activation PGs generated by COX-1 are considerably and to a much greater extent involved than PGs generated by COX-2. Social stress markedly diminishes the mediation of PGs generated by COX-1 but PGs synthesized by COX-2 do not substantially participate in the carbachol-induced HPA response.
乙酰胆碱能强烈刺激下丘脑 - 垂体 - 肾上腺（HPA）轴。胆碱能受体激动剂卡巴胆碱，经腹腔内（i.p.）或注入大脑侧脑室（i.c.v.）给予未麻醉大鼠，通过多种途径刺激HPA轴。本研究旨在确定：1）卡巴胆碱对参与刺激HPA轴的胆碱能毒蕈碱和/或烟碱受体的功能选择性；2）由组成型和诱导型环氧化酶（COX - 1和COX - 2）产生的前列腺素（PGs）在卡巴胆碱诱导的非应激大鼠以及暴露于社会拥挤应激7天（每笼24只，共6笼）的动物中促肾上腺皮质激素（ACTH）和皮质酮分泌中的作用。卡巴胆碱经i.c.v.或i.p.给药，胆碱能受体拮抗剂或环氧化酶同工酶拮抗剂在15分钟前经相同途径给药。最后一次注射后1小时采集躯干血用于测定ACTH和皮质酮。胆碱能受体拮抗剂阿托品（0.1微克，i.c.v.）完全消除了卡巴胆碱（2微克，i.c.v.）诱导的ACTH和皮质酮分泌，而选择性烟碱受体拮抗剂美加明（20微克，i.c.v.）不影响这种分泌。这一发现表明，卡巴胆碱作为一种选择性中枢胆碱能毒蕈碱受体激动剂刺激HPA轴。拥挤应激显著降低了给药后1小时测定的卡巴胆碱（0.2毫克/千克，i.p.）诱导的血浆ACTH和皮质酮水平。非选择性环氧化酶抑制剂吲哚美辛（2毫克/千克，i.p.）预处理显著降低了对照大鼠对卡巴胆碱（0.2毫克/千克，i.p.）的ACTH和皮质酮反应，并适度降低了应激大鼠的这些反应。COX - 1抑制剂吡罗昔康（0.2和2.0毫克/千克，i.p.）在对照大鼠中显著损害了卡巴胆碱诱导的ACTH和皮质酮反应，并在应激大鼠中显著降低了这些反应。选择性COX - 2阻滞剂化合物NS - 398（0.2和2.0毫克/千克，i.p.）在对照大鼠中大幅降低了卡巴胆碱诱导的激素分泌，但在应激大鼠中未显著改变这种分泌。这些结果表明，在卡巴胆碱诱导的HPA轴激活中，COX - 1产生的PGs比COX - 2产生的PGs参与程度更高且范围更广。社会应激显著降低了COX - 1产生的PGs的介导作用，但COX - 2合成的PGs在很大程度上不参与卡巴胆碱诱导的HPA反应。
