Gonzalez-Alvear G M, Werling L L
Department of Pharmacology, George Washington University Medical Center, Washington, D.C.
J Pharmacol Exp Ther. 1994 Oct;271(1):212-9.
Sigma receptors have been located in several areas of the brain that control motor function, including on the dopaminergic projections from substantia nigra to striatum. In the current study, the regulation of N-methyl-D-aspartate-stimulated [3H]dopamine release from slices of rat striatum by several sigma ligands has been tested. Both isomers of the benzomorphans SKF10,047 and pentazocine inhibited the stimulated release of dopamine in a concentration-related manner. All these compounds probably activate sigma and non-sigma receptors, including phencyclidine receptors, over the broad concentration ranges tested. However, concentrations of (+)pentazocine below about 100 nM appear to act solely through sigma receptors. This phase of inhibition was reversed by the sigma antagonist N-[-2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-[1- pyrimidinyl-1-piperazine butanol and by the sigma1-selective antagonist (1-(cyclopropylmethyl)-4-2'4"-fluorophenyl)-(2'-oxoethyl)piperi din e HBr. Neither of these antagonists affected stimulated release in the absence of (+)pentazocine. The synthetic sigma ligands 2-(4-morpholino)ethyl 1-phenylcyclohexane-1-carboxylate hydrochloride, 6-[6-(4-hydroxypiperidinyl)-hexoxy]-3-methylflavone hydrochloride and alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1- piperazine butanol enhanced NMDA-stimulated DA release significantly in the presence of (+)pentazocine. These drugs have affinity at non-sigma receptors as well, and their stimulatory effects may be mediated through these receptors along with nonreceptor mechanisms. Our findings on the regulation of dopamine support earlier assertions that sigma receptors may be important in the regulation of motor function.
σ受体已定位在大脑中控制运动功能的多个区域，包括从黑质到纹状体的多巴胺能投射区域。在当前研究中，测试了几种σ配体对N-甲基-D-天冬氨酸刺激的大鼠纹状体切片中[³H]多巴胺释放的调节作用。苯吗喃类化合物SKF10,047和喷他佐辛的两种异构体均以浓度相关的方式抑制多巴胺的刺激释放。在测试的较宽浓度范围内，所有这些化合物可能激活σ受体和非σ受体，包括苯环己哌啶受体。然而，低于约100 nM的(+)喷他佐辛浓度似乎仅通过σ受体起作用。这种抑制阶段可被σ拮抗剂N-[-2-(3,4-二氯苯基)乙基]-N-甲基-2-[1-嘧啶基-1-哌嗪丁醇和σ1选择性拮抗剂(1-(环丙基甲基)-4-(2',4"-二氟苯基)-(2'-氧代乙基)哌啶溴化氢逆转。在没有(+)喷他佐辛的情况下，这两种拮抗剂均不影响刺激释放。合成的σ配体盐酸2-(4-吗啉代)乙基1-苯基环己烷-1-羧酸酯、盐酸6-[6-(4-羟基哌啶基)-己氧基]-3-甲基黄酮和α-(4-氟苯基)-4-(5-氟-2-嘧啶基)-1-哌嗪丁醇在(+)喷他佐辛存在下显著增强NMDA刺激的DA释放。这些药物对非σ受体也有亲和力，它们的刺激作用可能通过这些受体以及非受体机制介导。我们关于多巴胺调节的研究结果支持了早期的论断，即σ受体可能在运动功能调节中起重要作用。
