Burmeister Melissa A, Ansonoff Michael A, Pintar John E, Kapusta Daniel R
Department of Pharmacology and Experimental Therapeutics, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA.
J Pharmacol Exp Ther. 2008 Sep;326(3):897-904. doi: 10.1124/jpet.107.135905. Epub 2008 Jun 6.
Intracerebroventricular administration of the opioid-like peptide nociceptin/orphanin FQ (N/OFQ) produces bradycardia, hypotension, and diuresis in mice. We hypothesized that these responses are solely caused by selective activation of central N/OFQ peptide (NOP) receptors. To test this premise, we first examined whether i.c.v. N/OFQ produced dose-dependent diuretic and cardiovascular depressor responses in commercially available C57BL/6 mice. Next, using doses established in these studies, we examined the renal excretory and cardiovascular responses to i.c.v. N/OFQ in conscious transgenic NOP receptor knockout mice (NOP(-/-)). In metabolic studies, i.c.v. N/OFQ, but not saline vehicle, dose-dependently increased urine output (V) in NOP(+/+); this response was significant at 3 nmol (N/OFQ, V = 0.39 +/- 0.10 ml/2 h; saline, 0.08 +/- 0.05 ml/2 h). The N/OFQ-evoked diuresis was absent in littermate NOP(-/-) (N/OFQ, V = 0.06 +/- 0.06 ml/2 h; saline, 0.03 +/- 0.03 ml/2 h). There were no significant changes in urinary sodium or potassium excretion or free water clearance in either group. In telemetry studies, i.c.v. N/OFQ dose dependently lowered heart rate (HR) and mean arterial pressure (MAP). At 3 nmol N/OFQ, both HR and MAP were reduced in NOP(+/+) (peak DeltaHR = -217 +/- 31 bpm; peak DeltaMAP =-47 +/- 7 mm Hg) compared with saline (peak DeltaHR =-14 +/- 5 bpm; peak DeltaMAP = 2 +/- 3 mm Hg). These N/OFQ-evoked bradycardic and hypotensive responses were absent in NOP(-/-) (peak DeltaHR =-13 +/- 17 bpm; peak DeltaMAP =-2 +/- 4 mm Hg, respectively). Basal 24-h cardiovascular and renal excretory function were not different between NOP(-/-) and NOP(+/+) mice. These results establish that the bradycardia, hypotension and diuresis produced by centrally administered N/OFQ are mediated by selective activation of NOP receptors.
脑室内注射阿片样肽孤啡肽（N/OFQ）可使小鼠出现心动过缓、低血压和利尿。我们推测这些反应完全是由中枢N/OFQ肽（NOP）受体的选择性激活引起的。为了验证这一前提，我们首先研究了脑室内注射N/OFQ是否能在市售的C57BL/6小鼠中产生剂量依赖性的利尿和心血管降压反应。接下来，我们使用这些研究中确定的剂量，研究了清醒的转基因NOP受体敲除小鼠（NOP(-/-)）对脑室内注射N/OFQ的肾脏排泄和心血管反应。在代谢研究中，脑室内注射N/OFQ而非生理盐水载体，能使NOP(+/+)小鼠的尿量（V）呈剂量依赖性增加；在3 nmol时这种反应显著（N/OFQ，V = 0.39 +/- 0.10 ml/2 h；生理盐水，0.08 +/- 0.05 ml/2 h）。同窝的NOP(-/-)小鼠未出现N/OFQ诱发的利尿反应（N/OFQ，V = 0.06 +/- 0.06 ml/2 h；生理盐水，0.03 +/- 0.03 ml/2 h）。两组的尿钠、钾排泄或自由水清除率均无显著变化。在遥测研究中，脑室内注射N/OFQ可使心率（HR）和平均动脉压（MAP）呈剂量依赖性降低。在3 nmol N/OFQ时，与生理盐水相比，NOP(+/+)小鼠的HR和MAP均降低（峰值ΔHR = -217 +/- 31次/分钟；峰值ΔMAP = -47 +/- 7 mmHg）（生理盐水组峰值ΔHR = -14 +/- 5次/分钟；峰值ΔMAP = 2 +/- 3 mmHg）。NOP(-/-)小鼠未出现这些N/OFQ诱发的心动过缓和低血压反应（峰值ΔHR = -13 +/- 17次/分钟；峰值ΔMAP分别为-2 +/- 4 mmHg）。NOP(-/-)和NOP(+/+)小鼠的基础24小时心血管和肾脏排泄功能无差异。这些结果表明，中枢给予N/OFQ所产生的心动过缓、低血压和利尿是由NOP受体的选择性激活介导的。
