Su X, Wachtel R E, Gebhart G F
Department of Pharmacology, College of Medicine, University of Iowa, Iowa City, 52242, USA.
J Neurophysiol. 1998 Dec;80(6):3112-9. doi: 10.1152/jn.1998.80.6.3112.
Inhibition of calcium currents in rat colon sensory neurons by kappa- but not mu- or delta-opioids. J. Neurophysiol. 80: 3112-3119, 1998. We previously reported that kappa-, but not mu- or delta-opioid receptor agonists (ORAs) have selective, potentially useful peripheral analgesic effects in visceral pain. To evaluate one potential site and mechanism by which these effects are produced, we studied opioid effects on high-voltage activated (HVA) Ca2+ currents in identified (Di-I) pelvic nerve sensory neurons from the S1 dorsal root ganglion (DRG). Results were compared with opioid effects on cutaneous neurons from L5 or L6 DRG. Di-I-labeled DRG cells were voltage clamped (perforated whole cell patch clamp), and HVA Ca2+ currents were evoked by depolarizing 240-ms test pulses to +10 mV from a holding potential of -60 mV. Neither mu-ORAs (morphine, 10(-6 )M, n = 16; [D-Ala2, N-Me-Phe4, Gly-ol5] enkephalin, 10(-6 )M, n = 12) nor delta-ORAs ([D-Pen2, D-Pen5] enkephalin, 10(-7 )M, n = 16; SNC-80, 10(-7 )M, n = 7) affected HVA Ca2+ currents in colon sensory neurons. In contrast, the kappa-ORAs U50, 488 (10(-6 )M), bremazocine (10(-6)M), and nalBzoH (10(-6 )M) significantly attenuated HVA Ca2+ currents in colon sensory neurons; effects on cutaneous sensory neurons were variable. A nonreceptor selective concentration of naloxone (10(-5 )M) and nor-BNI (10(-6 )M), a selective kappa-opioid receptor antagonist, reversed the inhibitory effect of kappa-ORAs. In the presence of N-, P-, or Q-, but not L-type Ca2+ channel antagonists, the effect of U50,488 on HVA Ca2+ currents was significantly reduced. Pretreatment with pertussis toxin (PTX) prevented the inhibition by U50,488. These results suggest that kappa-opioid receptors are coupled to multiple HVA Ca2+ channels in colon sensory neurons by a PTX-sensitive G protein pathway. We conclude that inhibition of Ca2+ channel function likely contributes in part to the peripheral analgesic action of kappa-ORAs in visceral nociception.
κ-阿片类药物而非μ-或δ-阿片类药物对大鼠结肠感觉神经元钙电流的抑制作用。《神经生理学杂志》80: 3112 - 3119, 1998年。我们先前报道，κ-阿片类受体激动剂（ORAs）而非μ-或δ-阿片类受体激动剂在内脏痛中有选择性的、可能有用的外周镇痛作用。为评估产生这些作用的一个潜在部位和机制，我们研究了阿片类药物对来自S1背根神经节（DRG）的已鉴定（Di-I）盆神经感觉神经元中高压激活（HVA）Ca2+电流的影响。将结果与阿片类药物对L5或L6 DRG皮肤感觉神经元的影响进行比较。用Di-I标记的DRG细胞进行电压钳制（穿孔全细胞膜片钳），通过将240毫秒的测试脉冲从 - 60 mV的钳制电位去极化到 +10 mV来诱发HVA Ca2+电流。μ-ORAs（吗啡，10(-6)M，n = 16；[D - Ala2，N - Me - Phe4，Gly - ol5]脑啡肽，10(-6)M，n = 12）和δ-ORAs（[D - Pen2，D - Pen5]脑啡肽，10(-7)M，n = 16；SNC - 80，10(-7)M，n = 7）均未影响结肠感觉神经元中的HVA Ca2+电流。相比之下，κ-ORAs U50,488（10(-6)M）、布马佐辛（10(-6)M）和纳布佐辛（10(-6)M）显著减弱了结肠感觉神经元中的HVA Ca2+电流；对皮肤感觉神经元的影响则各不相同。非受体选择性浓度的纳洛酮（10(-5)M）和选择性κ-阿片类受体拮抗剂nor - BNI（10(-6)M）可逆转κ-ORAs的抑制作用。在存在N -、P -或Q -型而非L -型钙通道拮抗剂的情况下，U50,488对HVA Ca2+电流的作用显著降低。用百日咳毒素（PTX）预处理可防止U50,488的抑制作用。这些结果表明，κ-阿片类受体通过PTX敏感的G蛋白途径与结肠感觉神经元中的多种HVA Ca2+通道偶联。我们得出结论，Ca2+通道功能的抑制可能部分有助于κ-ORAs在内脏痛觉感受中的外周镇痛作用。
