κ-Opioid receptor antagonism reverses heroin withdrawal-induced hyperalgesia in male and female rats.
κ-Opioid receptor antagonism reverses heroin withdrawal-induced hyperalgesia in male and female rats.
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DOI：
10.1016/j.ynstr.2021.100325
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发表时间：
2021-05
影响因子：
5
通讯作者：
Vendruscolo LF
中科院分区：
文献类型：
--
作者：
Marchette RCN;Gregory-Flores A;Tunstall BJ;Carlson ER;Jackson SN;Sulima A;Rice KC;Koob GF;Vendruscolo LF
虽然阿片类药物是强效镇痛剂，但长期使用阿片类药物的后果是戒断期间的痛觉过敏，这可能导致阿片类药物滥用。强啡肽是κ-阿片受体（KORs）的内源性配体，在阿片依赖大鼠和慢性疼痛动物模型中上调。然而，KORs在阿片类药物戒断诱导的痛觉过敏中的作用仍有待确定。我们假设KOR拮抗作用可以逆转阿片依赖大鼠阿片戒断诱导的痛觉过敏。雄性和雌性Wistar大鼠每天接受海洛因注射（2-6 mg/kg，SC），并在戒断后4-6 h在电子von Frey试验中检测机械敏感性。雌性大鼠需要比雄性大鼠更多的海洛因才能达到海洛因诱导的镇痛和痛觉过敏的可比水平（6 mg/kg vs. 2 mg/kg）。一旦建立痛觉过敏，我们测试了KOR拮抗剂nor-binaltorphimine（norBNI; 30 mg/kg，SC）和5′-guanidinonaltrindole（5′GNTI; 30 mg/kg，SC）的作用。当动物在整个实验中每周五次继续接受每日海洛因治疗（或重复盐水组中的盐水治疗）时，两种KOR拮抗剂都逆转了海洛因戒断诱导的痛觉过敏。norBNI的抗痛觉过敏作用在雄性中比在雌性中更持久（14天vs. 7天），而5′GNTI在雌性中的作用比在雄性中更持久（14天vs. 4天）。5′GNTI的行为效应与24 h时测定的脑中5′GNTI水平高于血浆中的5′GNTI水平一致，而当血浆中5′ GNTI水平高于脑中时，5′GNTI在治疗后30 min时不能逆转痛觉过敏。最后，我们测试了5′GNTI对纳洛酮诱导的和自发的阿片类戒断症状的影响，发现在雄性或雌性大鼠中均无影响。这些研究结果表明，在两种性别的大鼠中观察到的海洛因戒断诱导的痛觉过敏的KORs的功能作用。
Although opioids are potent analgesics, a consequence of chronic opioid use is hyperalgesia during withdrawal, which may contribute to opioid misuse. Dynorphin, the endogenous ligand of κ-opioid receptors (KORs), is upregulated in opioid-dependent rats and in animal models of chronic pain. However, the role of KORs in opioid withdrawal-induced hyperalgesia remains to be determined. We hypothesized that KOR antagonism would reverse opioid withdrawal-induced hyperalgesia in opioid-dependent rats. Male and female Wistar rats received daily injections of heroin (2–6 mg/kg, SC) and were tested for mechanical sensitivity in the electronic von Frey test 4–6 h into withdrawal. Female rats required significantly more heroin than male rats to reach comparable levels of both heroin-induced analgesia and hyperalgesia (6 mg/kg vs. 2 mg/kg). Once hyperalgesia was established, we tested the effects of the KOR antagonists nor-binaltorphimine (norBNI; 30 mg/kg, SC) and 5′-guanidinonaltrindole (5′GNTI; 30 mg/kg, SC). When the animals continued to receive their daily heroin treatment (or saline treatment in the repeated saline group) five times per week throughout the experiment, both KOR antagonists reversed heroin withdrawal-induced hyperalgesia. The anti-hyperalgesia effect of norBNI was more prolonged in males than in females (14 days vs. 7 days), whereas 5′GNTI had more prolonged effects in females than in males (14 days vs. 4 days). The behavioral effects of 5′GNTI coincided with higher 5′GNTI levels in the brain than in plasma when measured at 24 h, whereas 5′GNTI did not reverse hyperalgesia at 30 min posttreatment when 5′GNTI levels were higher in plasma than in the brain. Finally, we tested the effects of 5′GNTI on naloxone-induced and spontaneous signs of opioid withdrawal and found no effect in either male or female rats. These findings indicate a functional role for KORs in heroin withdrawal-induced hyperalgesia that is observed in rats of both sexes.
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影响因子：
3.4
作者：
Comer, Sandra D.;Cooper, Ziva D.;Kowalczyk, William J.;Sullivan, Maria A.;Evans, Suzette M.;Bisaga, Adam M.;Vosburg, Suzanne K.
通讯作者：
Vosburg, Suzanne K.
影响因子：
2.9
作者：
Doyle HH;Murphy AZ
通讯作者：
Murphy AZ
影响因子：
2.3
作者：
Carcoba, Luis M.;Contreras, Arturo E.;Meagher, Mary W.
通讯作者：
Meagher, Mary W.
影响因子：
4.7
作者：
Chartoff, Elena;Sawyer, Allison;Rachlin, Anna;Potter, Dave;Pliakas, Andrea;Carlezon, William A.
通讯作者：
Carlezon, William A.
影响因子：
3.6
作者：
Cicero, TJ;Aylward, SC;Meyer, ER
通讯作者：
Meyer, ER