Patel S, Hutson P H
Merck Sharpe and Dohme Research Laboratories, Neuroscience Research Centre, Terlings Park, Harlow, Essex, UK.
Eur J Pharmacol. 1994 Apr 1;255(1-3):25-32. doi: 10.1016/0014-2999(94)90078-7.
Central administration of galanin in the mouse dose-dependently blocked the hypothermia induced by the muscarinic receptor agonist, 2-ethyl 8-methyl-2,8-diazospiro[4,5]decan-1,3-dion hydrobromide, RS86 (minimum effective dose, MED = 3 nmol) and the acetylcholinesterase inhibitor tetrahydroaminoacridine, (MED = 3 nmol). This inhibitory effect was reversed over the dose range (0.1, 0.3, 1, 3 nmol) by the galanin receptor antagonist galantide (MED = 0.3 nmol). Furthermore, the ATP-sensitive K+ channel blockers glibenclamide (MED = 1 nmol) and gliquidone (10 nmol) both prevented the inhibitory effects of galanin on RS86 induced hypothermia. Glibenclamide (10 nmol) also reversed the inhibitory effects of galanin on tetrahydroaminoacridine induced hypothermia. Preincubation of rat cortical membranes with galanin (10 nM, 1000 nM) in vitro had no effect on binding affinity, receptor number or pharmacology of the rat cortical muscarinic receptor. In contrast to the high affinity of glibenclamide, galanin only weakly displaced [3H]glibenclamide binding in mouse whole brain homogenates (36% at 10 microM). These studies suggest that the inhibitory effect of galanin on cholinergically mediated hypothermia induced by RS86 and tetrahydroaminoacridine may be exerted via an action at ATP-sensitive K+ channels but is unlikely to be acting directly at the site labelled by [3H]glibenclamide.
向小鼠中枢给药甘丙肽，剂量依赖性地阻断了毒蕈碱受体激动剂2-乙基-8-甲基-2,8-二氮杂螺[4,5]癸烷-1,3-二酮氢溴酸盐（RS86，最小有效剂量，MED = 3 nmol）和乙酰胆碱酯酶抑制剂他克林（MED = 3 nmol）诱导的体温过低。在剂量范围（0.1、0.3、1、3 nmol）内，甘丙肽受体拮抗剂加兰他敏（MED = 0.3 nmol）可逆转这种抑制作用。此外，ATP敏感性钾通道阻滞剂格列本脲（MED = 1 nmol）和格列喹酮（10 nmol）均能预防甘丙肽对RS86诱导的体温过低的抑制作用。格列本脲（10 nmol）也能逆转甘丙肽对他克林诱导的体温过低的抑制作用。在体外将大鼠皮质膜与甘丙肽（10 nM、1000 nM）预孵育，对大鼠皮质毒蕈碱受体的结合亲和力、受体数量或药理学无影响。与格列本脲的高亲和力相反，甘丙肽在小鼠全脑匀浆中仅微弱地取代[3H]格列本脲的结合（10 μM时为36%）。这些研究表明，甘丙肽对RS86和他克林诱导的胆碱能介导的体温过低的抑制作用可能是通过作用于ATP敏感性钾通道发挥的，但不太可能直接作用于[3H]格列本脲标记的位点。
