The prolactin receptor long isoform regulates nociceptor sensitization and opioid-induced hyperalgesia selectively in females.
The prolactin receptor long isoform regulates nociceptor sensitization and opioid-induced hyperalgesia selectively in females.
复制标题
DOI：
10.1126/scitranslmed.aay7550
复制
发表时间：
2020-02-05
影响因子：
17.1
通讯作者：
Porreca F
中科院分区：
文献类型：
--
作者：
Chen Y;Moutal A;Navratilova E;Kopruszinski C;Yue X;Ikegami M;Chow M;Kanazawa I;Bellampalli SS;Xie J;Patwardhan A;Rice K;Fields H;Akopian A;Neugebauer V;Dodick D;Khanna R;Porreca F
疼痛在女性中更为普遍，原因尚不清楚。我们已经确定了一种机制，无损伤的伤害性感受器敏化和阿片类药物诱导的痛觉过敏（OIH）促进催乳素（PRL）在女性。PRL信号通过相互抑制的长（PRLR-L）和短（PRLR-S）受体亚型，PRLR-S激活诱导神经元兴奋性。PRL和PRLR表达在女性中较高。CRISPR介导的PRLR-L编辑促进了依赖循环PRL的幼稚未受伤雌性小鼠的伤害感受器敏化和异常性疼痛。阿片类药物，而不是创伤诱导的神经损伤，减少PRLR-L促进OIH通过激活PRLR-S在雌性小鼠。PRLR-L和PRLR-S（总PRLR）的删除防止，而PRLR-L过表达拯救建立OIH选择性的女性。卡麦角林（一种多巴胺D2激动剂）对循环PRL的抑制仅在雌性动物中上调PRLR-L并预防OIH。因此，PRLR-L同种型可保护女性免受PRL促进的疼痛。限制PRL/PRLR-S信号传导通路或靶向PRLR的基因疗法可能有效地以女性选择性方式减轻疼痛。
Pain is more prevalent in women for reasons that remain unclear. We have identified a mechanism of injury-free nociceptor sensitization and opioid-induced hyperalgesia (OIH) promoted by prolactin (PRL) in females. PRL signals through mutually inhibitory long (PRLR-L) and short (PRLR-S) receptor isoforms, and PRLR-S activation induces neuronal excitability. PRL and PRLR expression were higher in females. CRISPR-mediated editing of PRLR-L promoted nociceptor sensitization and allodynia in naïve, uninjured female mice that depended on circulating PRL. Opioids, but not trauma-induced nerve injury, decreased PRLR-L promoting OIH through activation of PRLR-S in female mice. Deletion of both PRLR-L and PRLR-S (total PRLR) prevented, whereas PRLR-L overexpression rescued established OIH selectively in females. Inhibition of circulating PRL with cabergoline, a dopamine D2 agonist, up-regulated PRLR-L and prevented OIH only in females. The PRLR-L isoform therefore confers protection against PRL-promoted pain in females. Limiting PRL/PRLR-S signaling pharmacologically or with gene therapies targeting the PRLR may be effective for reducing pain in a female-selective manner.
登录
查看更多内容
影响因子：
4.8
作者：
Belugin, Sergei;Diogenes, Anibal R.;Akopian, Armen N.
通讯作者：
Akopian, Armen N.
影响因子：
2
作者：
EGUCHI, K;KAWAMOTO, K;KURISU, K
通讯作者：
KURISU, K
影响因子：
5.3
作者：
Diogenes, Anibal;Patwardhan, Amol M.;Hargreaves, Kenneth M.
通讯作者：
Hargreaves, Kenneth M.
影响因子：
4.8
作者：
DEYO, SN;SWIFT, RM;FANG, VS
通讯作者：
FANG, VS
影响因子：
25
作者：
Ferrini F;Trang T;Mattioli TA;Laffray S;Del'Guidice T;Lorenzo LE;Castonguay A;Doyon N;Zhang W;Godin AG;Mohr D;Beggs S;Vandal K;Beaulieu JM;Cahill CM;Salter MW;De Koninck Y
通讯作者：
De Koninck Y