Millan M J, Colpaert F C
Neurobiology Division, Fondax, Groupe de Recherche Servier, Puteaux, France.
J Pharmacol Exp Ther. 1991 Mar;256(3):983-92.
This study examined the influence of s.c. administration of 5-hydroxytryptamine (HT)1A agonists upon the antinociceptive action of s.c. injected morphine in tail-flick tests to noxious heat and pressure. The selective 5-HT1A agonist, (+-)-8-hydroxy-diprolaminotetralin HBr (8-OH-DPAT), dose-dependently antagonized morphine-induced antinociception (MIA) without affecting the latency to respond when applied alone. In the presence of increasing doses of 8-OH-DPAT (0.16-0.63 mg/kg), the morphine dose-response curve was shifted progressively in parallel to the right and the maximal effect of morphine was not altered; Schild analysis yielded a slope of close to -1.0. 8-OH-DPAT both prevented and reversed the action of morphine. The action of 8-OH-DPAT was reversible (at 24 hr). In distinction, 8-OH-DPAT neither blocked morphine-induced Straub tail nor precipitated withdrawal in morphine-dependent animals; thus, it lacked opioid-antagonist properties. The antagonism of MIA by 8-OH-DPAT was mimicked by additional drugs acting as high efficacy 5-HT1A agonists: lisuride, 5-methoxy-N,N-dimethyltryptamine hydrogen oxalate, RU 24969 [methoxy-3-(1,2,3.6-tetrahydropyridin-4-yl)-1H-indole] and d-lysergic acid diethylamide. In contrast, the 5-HT1B/1C agonist, TFMPP m-trifluromethylphenylpiperazine HCl, and the 5-HT1C/2 agonist, DOI (+-)-2,5-dimethoxy-4-iodophenyl-2-aminopropane HCI, were ineffective. The putative selective 5-HT1A antagonists, BMY 7378 [(8-[-[4-(2-,ethoxyphenyl)-1-piperazinyl]ethyl]-8-azaspirol[4]- decane-7,9-dione-2-HCL] and spiperone, did not reduce MIA. Indeed, BMY 7378 blocked the ability of 8-OH-DPAT to antagonize MIA. Under the present conditions, agonists and antagonists at adrenergic and dopaminergic receptors did not attenuate MIA. These data show that, over a certain range of doses, the systemic administration of 8-OH-DPAT and other high efficacy 5-HT1A agonists functionally antagonizes the antinociceptive action of systemically applied morphine in a competitive-like manner. It is suggested that 5-HT1A receptors play an important role in the modulation of opioidergic antinociceptive mechanisms.
本研究在对有害热和压力的甩尾试验中，检测了皮下注射5-羟色胺（HT）1A激动剂对皮下注射吗啡的抗伤害感受作用的影响。选择性5-HT1A激动剂（±）-8-羟基二丙氨四氢萘溴化物（8-OH-DPAT）剂量依赖性地拮抗吗啡诱导的抗伤害感受（MIA），单独应用时不影响反应潜伏期。在8-OH-DPAT剂量增加（0.16 - 0.63mg/kg）的情况下，吗啡剂量 - 反应曲线逐渐平行右移，吗啡的最大效应未改变；Schild分析得出斜率接近 -1.0。8-OH-DPAT既能预防也能逆转吗啡的作用。8-OH-DPAT的作用是可逆的（24小时后）。相比之下，8-OH-DPAT既不阻断吗啡诱导的Straub尾反应，也不会使吗啡依赖动物出现戒断反应；因此，它不具有阿片类拮抗剂特性。其他作为高效5-HT1A激动剂的药物：利苏瑞肽、5-甲氧基 - N，N - 二甲基色胺草酸氢盐、RU 24969 [甲氧基 - 3 -（1,2,3,6 - 四氢吡啶 - 4 - 基）-1H - 吲哚]和d - 麦角酸二乙酰胺，均可模拟8-OH-DPAT对MIA的拮抗作用。相反，5-HT1B/1C激动剂TFMPP盐酸间三氟甲基苯基哌嗪和5-HT1C/2激动剂DOI（±）-2,5 - 二甲氧基 - 4 - 碘苯基 - 2 - 氨基丙烷盐酸盐无效。假定的选择性5-HT1A拮抗剂BMY 7378 [（8 - [-[4 -（2 - 乙氧基苯基）-1 - 哌嗪基]乙基] - 8 - 氮杂螺[4.5]癸烷 - 7,9 - 二酮 - 2 - HCL]和螺哌隆，并未降低MIA。实际上，BMY 7378阻断了8-OH-DPAT拮抗MIA的能力。在当前条件下，肾上腺素能和多巴胺能受体的激动剂和拮抗剂均未减弱MIA。这些数据表明，在一定剂量范围内，全身给予8-OH-DPAT和其他高效5-HT1A激动剂以类似竞争性的方式在功能上拮抗全身应用吗啡的抗伤害感受作用。提示5-HT1A受体在阿片类抗伤害感受机制的调节中起重要作用。
