Dissociable effects of the kappa opioid receptor agonist nalfurafine on pain/itch-stimulated and pain/itch-depressed behaviors in male rats.
Dissociable effects of the kappa opioid receptor agonist nalfurafine on pain/itch-stimulated and pain/itch-depressed behaviors in male rats.
复制标题
DOI：
10.1007/s00213-017-4758-7
复制
发表时间：
2018-01
影响因子：
3.4
通讯作者：
Negus SS
中科院分区：
文献类型：
--
作者：
Lazenka ML;Moerke MJ;Townsend EA;Freeman KB;Carroll FI;Negus SS
纳呋芬是一种G蛋白信号偏向的kappa阿片受体(KOR)激动剂，在日本被批准用于尿毒症瘙痒的二线治疗。目前，无论是纳呋芬还是其他任何KOR激动剂都没有被批准用于治疗疼痛，但最近的证据表明，G蛋白信号偏向的KOR激动剂可能有希望作为候选止痛药/止痒药，与无偏向或β-arrestin信号偏向的KOR激动剂相比，副作用减少。这项研究使用先前用于评估其他候选镇痛剂的疼痛刺激和疼痛抑制行为的分析，比较了纳呋芬在大鼠中的效果。在瘙痒刺激和瘙痒抑制行为的补充试验中也检验了呋喃西林的作用。在雄性SD大鼠上，腹腔注射乳酸(IP酸)和皮下注射5-羟色胺(ID-5-HT)分别作为刺激性刺激和瘙痒刺激，以刺激拉伸(IP酸)或抓挠(ID-5-HT)或抑制在颅内自我刺激试验(ICSS；两种刺激)中正强化的操作者反应。在减少IP酸刺激的伸展和ID5-HT刺激的抓挠方面，呋喃西芬的作用是相同的；然而，减少这些疼痛/瘙痒刺激行为的剂量也降低了控制ICSS的性能。此外，纳呋芬不能减轻ip酸或ID5-HT引起的ICSS抑制。这些结果表明，纳呋芬引起的疼痛/瘙痒刺激行为的减少可能反映了动机行为的非选择性减少，而不是针对这里使用的伤害性和瘙痒刺激的止痛或止痒。这一结论与缺乏临床资料的纳呋芬止痛药和较弱的临床资料是一致的。呋喃西林对G蛋白信号的偏向可能不足以用于临床安全可靠的止痛或止痒。
Nalfurafine is a G-protein-signaling-biased kappa opioid receptor (KOR) agonist approved in Japan for second-line treatment of uremic pruritus. Neither nalfurafine nor any other KOR agonist is currently approved anywhere for treatment of pain, but recent evidence suggests that G-protein-signaling-biased KOR agonists may have promise as candidate analgesics/antipruritics with reduced side effects compared to nonbiased or β-arrestin-signaling-biased KOR agonists. This study compared nalfurafine effects in rats using assays of pain-stimulated and pain-depressed behavior used previously to evaluate other candidate analgesics. Nalfurafine effects were also examined in complementary assays of itch-stimulated and itch-depressed behavior. Intraperitoneal lactic acid (IP acid) and intradermal serotonin (ID 5HT) served as noxious and pruritic stimuli, respectively, in male Sprague Dawley rats to stimulate stretching (IP acid) or scratching (ID 5HT) or to depress positively reinforced operant responding in an assay of intracranial self-stimulation (ICSS; both stimuli). Nalfurafine was equipotent to decrease IP acid-stimulated stretching and ID 5HT-stimulated scratching; however, doses of nalfurafine that decreased these pain/itch-stimulated behaviors also decreased control ICSS performance. Moreover, nalfurafine failed to alleviate either IP acid- or ID 5HT-induced depression of ICSS. These results suggest that nalfurafine-induced decreases in pain/itch-stimulated behaviors may reflect nonselective decreases in motivated behavior rather than analgesia or antipruritus against the noxious and pruritic stimuli used here. This conclusion agrees with the absence of clinical data for nalfurafine analgesia and the weak clinical data for nalfurafine antipruritus. Nalfurafine bias for G-protein signaling may not be sufficient for clinically safe and reliable analgesia or antipruritus.
登录
查看更多内容
影响因子：
4.2
作者：
Johnson, Matthew W.;MacLean, Katherine A.;Reissig, Chad J.;Prisinzano, Thomas E.;Griffiths, Roland R.
通讯作者：
Griffiths, Roland R.
影响因子：
5
作者：
DiMattio KM;Ehlert FJ;Liu-Chen LY
通讯作者：
Liu-Chen LY
影响因子：
14.8
作者：
Carlezon, William A., Jr.;Chartoff, Elena H.
通讯作者：
Chartoff, Elena H.
DOI：
10.1007/978-3-662-44605-8_16
发表时间：
2015-01-01
期刊：
PHARMACOLOGY OF ITCH
影响因子：
--
作者：
Cowan, Alan;Kehner, George B.;Inan, Saadet
通讯作者：
Inan, Saadet
DOI：
10.2147/ccid.s55942
发表时间：
2015
期刊：
Clinical, cosmetic and investigational dermatology
影响因子：
--
作者：
Inui S
通讯作者：
Inui S