Su X, Sengupta J N, Gebhart G F
Department of Pharmacology, College of Medicine, The University of Iowa, Iowa City 52242, USA.
J Neurophysiol. 1997 Aug;78(2):1003-12. doi: 10.1152/jn.1997.78.2.1003.
The aim of this study was to examine the effects of kappa-opioid receptor selective agonists on responses of mechanosensitive afferent fibers in the pelvic nerve. Single-fiber recordings were made from pelvic nerve afferents in the decentralized S1 dorsal root of the rat. A total of 572 afferent fibers in the S1 dorsal root were identified by electrical stimulation of the pelvic nerve; 252 (44%) responded to noxious colorectal distension (CRD; 80 mmHg). Of these 252 fibers that responded to CRD, 100 were studied further. All 100 fibers gave monotonic increases in firing to increasing pressures of CRD. Eighty-eight fibers had low thresholds for response (mean: 3 mmHg) and 12 fibers had high-thresholds for response (mean: 28 mmHg). Responses of 17 fibers also were tested after instillation of 5% mustard oil (MO) into the colon. The resting activity of 16/17 fibers significantly increased after MO instillation; 13 (77%) also exhibited sensitization of responses to graded CRD when tested 30 min after intracolonic MO instillation. The effects of kappa1-opioid receptor preferring agonists (U50,488H, U69,593 and U62,066), the kappa2-opioid receptor preferring agonist bremazocine, and the kappa3-opioid receptor preferring agonist naloxone benzoylhydrazone (nalBzoH) were tested on responses of 64 mechanosensitive afferent fibers to noxious CRD. All five agonists dose-dependently inhibited afferent fiber responses to noxious CRD. Doses producing inhibition to 50% of the control response to CRD did not differ among the five agonists, ranging from approximately 4 to 15 mg/kg. The effects of kappa1, kappa2, and kappa3 receptor agonists were attenuated by naloxone; two kappa-opioid receptor-selective antagonists were ineffective. There were no differences in the dose-response relationships of these drugs for fibers recorded from untreated and irritant-treated colons. Conduction velocities of the fibers remained unaffected after high doses of all tested agonists. In an in vitro study, U50,488 (10(-4) M) did not produce any significant change in the tension of colonic smooth muscle. These results document that responses of mechanosensitive pelvic nerve afferent fibers innervating the colon are inhibited by kappa-opioid receptor agonists having varying affinities for putative kappa-opioid receptor subtypes. The inhibitory effects of these drugs likely are mediated by an action at receptors associated with the afferent fibers. The receptor at which these effects are produced is kappa-opioid-like but clearly different from the kappa-opioid receptor characterized in the CNS and is perhaps an orphan receptor.
本研究的目的是检测κ-阿片受体选择性激动剂对盆神经中机械敏感传入纤维反应的影响。在大鼠S1背根去传入化的情况下，对盆神经传入纤维进行单纤维记录。通过电刺激盆神经，在S1背根中总共识别出572条传入纤维；252条（44%）对有害性结直肠扩张（CRD；80 mmHg）有反应。在这252条对CRD有反应的纤维中，进一步研究了100条。所有100条纤维对逐渐增加的CRD压力产生单调的放电增加。88条纤维反应阈值低（平均：3 mmHg），12条纤维反应阈值高（平均：28 mmHg）。在向结肠内注入5%芥子油（MO）后，还测试了17条纤维的反应。17条纤维中有16条在注入MO后静息活动显著增加；在结肠内注入MO 30分钟后进行测试时，13条（77%）对分级CRD的反应也表现出敏感化。在64条机械敏感传入纤维对有害性CRD的反应上，测试了偏爱κ1-阿片受体的激动剂（U50,488H、U69,593和U62,066）、偏爱κ2-阿片受体的激动剂布马佐辛以及偏爱κ3-阿片受体的激动剂纳洛酮苯甲酰腙（nalBzoH）的作用。所有五种激动剂均剂量依赖性地抑制传入纤维对有害性CRD的反应。产生对CRD对照反应50%抑制作用的剂量在这五种激动剂之间没有差异，范围约为4至15 mg/kg。κ1、κ2和κ3受体激动剂的作用被纳洛酮减弱；两种κ-阿片受体选择性拮抗剂无效。这些药物对未处理结肠和经刺激处理结肠记录的纤维的剂量反应关系没有差异。在高剂量的所有测试激动剂作用后，纤维的传导速度仍未受影响。在一项体外研究中，U50,488（10⁻⁴ M）未使结肠平滑肌张力产生任何显著变化。这些结果表明，支配结肠的机械敏感盆神经传入纤维的反应受到对假定的κ-阿片受体亚型具有不同亲和力的κ-阿片受体激动剂的抑制。这些药物的抑制作用可能是通过作用于与传入纤维相关的受体介导的。产生这些作用的受体类似κ-阿片受体，但明显不同于中枢神经系统中所描述的κ-阿片受体，可能是一种孤儿受体。
