Sex differences in micro-opioid receptor expression in the rat midbrain periaqueductal gray are essential for eliciting sex differences in morphine analgesia.
Sex differences in micro-opioid receptor expression in the rat midbrain periaqueductal gray are essential for eliciting sex differences in morphine analgesia.
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DOI：
10.1523/jneurosci.4123-08.2008
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发表时间：
2008-12-24
期刊：
影响因子：
--
通讯作者：
Murphy AZ
中科院分区：
文献类型：
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作者：
Loyd DR;Wang X;Murphy AZ
阿片类麻醉剂是缓解持续性疼痛最常用的处方药；然而，越来越明显的是，与男性相比，吗啡对女性的药效明显较弱。吗啡主要与μ阿片受体（MOR）结合，而中脑导水管周围灰质（PAG）含有大量表达MOR的神经元。PAG通过其向下投射至延髓头端腹内侧及脊髓背角，被认为是阿片类镇痛作用的关键神经基质。我们假设PAG中MOR的表达存在性别差异，且这些性别差异导致了所观察到的吗啡药效的性别差异。通过免疫组织化学方法，我们发现，与处于动情周期的雌性相比，雄性在PAG腹外侧的MOR表达显著更高，而在发情前期雌性中观察到的表达水平最低。完全弗氏佐剂（CFA）诱导的炎性疼痛在雄性和雌性中均产生热痛觉过敏，将吗啡微量注射到雄性PAG腹外侧可显著逆转这种情况；这种效果明显强于发情前期和发情期的雌性。仅对雄性PAG腹外侧表达MOR的神经元进行选择性损伤，会导致全身应用吗啡的效果显著降低，且这种降低与PAG腹外侧MOR的表达水平呈正相关。综上所述，这些结果为吗啡药效的性别差异提供了一种机制。
Opioid-based narcotics are the most widely prescribed therapeutic agent for the alleviation of persistent pain; however, it is becoming increasingly clear that morphine is significantly less potent in women compared to men. Morphine primarily binds to mu opioid receptors (MOR), and the periaqueductal gray (PAG) contains a dense population of MOR-expressing neurons. Via its descending projections to the rostral ventromedial medulla and the dorsal horn of the spinal cord, the PAG is considered an essential neural substrate for opioid-based analgesia. We hypothesized that MOR expression in the PAG was sexually dimorphic, and that these sex differences contribute to the observed sex differences in morphine potency. Using immunohistochemistry, we report that males had a significantly higher expression of MOR in the ventrolateral PAG compared to cycling females, while the lowest level of expression was observed in proestrus females. CFA-induced inflammatory pain produced thermal hyperalgesia in both males and females that was significantly reversed in males with a microinjection of morphine into the ventrolateral PAG; this effect was significantly greater than that observed in proestrus and estrus females. Selective lesions of MOR-expressing neurons in the ventrolateral PAG resulted in a significant reduction in the effects of systemic morphine in males only, and this reduction was positively correlated with the level of MOR expression in the ventrolateral PAG. Together, these results provide a mechanism for sex differences in morphine potency.