ROLE OF ESTROGEN AND PROGESTERONE IN SCI PAIN

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。大多数脊髓损伤(SCI)患者在完全和部分损伤后会出现慢性中枢性疼痛，包括水平痛觉异常(在损伤水平及其上方触摸皮肤体的疼痛)。利用新近建立的大鼠电生理模型(活体)研究慢性脊髓损伤对脊髓上神经元反应的影响，本实验室获得的新数据表明，激素周期正常的雌性大鼠脊髓损伤后，与雄性/去卵巢大鼠相比，脊髓损伤后水平痛觉异常的发展明显减少。这增加了黄体酮和/或雌激素对脊髓损伤引起的疼痛起到治疗作用的可能性。我们也有证据支持这一假说，在水平超敏，如果它发展，可能是由于背外侧象限下行通路的损伤，以及腹外象限至少一部分上升束(S)的保留，该上升束将来自损伤水平正上方的皮肤体的信息传递到更高的中枢。此外，初步数据表明，当痛觉异常发展时，循环孕酮和/或雌激素可能会加剧疼痛，这在脑干神经元的反应性中明显可见。这种恶化与人类痛觉阈值周期相关变化的许多情况的发现是一致的。因此，将根据荷尔蒙状态的实验变化和损伤/保留的特定模式的变化来检查在水平上痛觉异常的发展和持续。潜在的机制可能包括丘脑(参与最终导致疼痛的输入处理的重要区域)神经元反应的变化，这将与伴随这些变化的伴随行为体征(即痛觉异常)进行比较。因此，这一建议的一个独特之处是采用了多学科方法，即对每种动物使用电生理、行为和解剖学测量。这项拟议的研究将检查与卵巢激素相关的潜在机制，这些机制阻止了这种发展，并有助于这种与临床相关的水平上的痛觉异常的永久存在。因此，这些研究将有助于更好地了解SCI疼痛的神经机制，并将卵巢激素确定为易于调节以预防和治疗SCI相关疼痛的靶点。这一点非常重要，因为目前的药物治疗和手术干预是不够的。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Chronic central pain develops in the majority of spinal cord injury (SCI) patients following complete and partial injuries, including at level allodynia (pain to touch in dermatomes at and just above the level of injury). Using a recently developed electrophysiological rat model (in vivo) for investigating the effects of chronic SCI on responses in supraspinal neurons, new data from our lab was obtained which indicates that the development of at level allodynia is dramatically reduced after SCI in female rats with normal hormonal cycles compared to males/ovariectomized females. This raises the possibility that progesterone and/or estrogen could play therapeutic roles for SCI-induced pain. We also have evidence supporting the hypothesis that at level allodynia, if and when it develops, may result from damage to descending pathways in the dorsolateral quadrant in combination with sparing of at least a portion of ascending tract(s) in the ventrolateral quadrant that transmit, to higher centers, the information from dermatomes just above the level of injury. Moreover, preliminary data indicate that the allodynia, when it develops, may be exacerbated by circulating progesterone and/or estrogen, which is clearly seen in the responsiveness of brainstem neurons. This exacerbation is consistent with findings for numerous conditions with cycle related changes in pain thresholds in humans. Thus, the development and perpetuation of at level allodynia will be examined relative to experimental variations of hormonal status and variations in specific patterns of damage/sparing. The underlying mechanism may include changes in the responses of neurons in the thalamus (an important region involved in the processing of inputs that ultimately lead to pain), which will be compared to the concomitant behavioral signs that accompany these changes (i.e., allodynia). Thus, a unique feature of this proposal is the multidisciplinary approach that is taken, i.e., using electrophysiological, behavioral and anatomical measures for each animal. The proposed research will examine the underlying mechanisms related to ovarian hormones that prevent the development and contribute to the perpetuation of this clinically-relevant at level allodynia. Therefore, these studies will lead to a better understanding of the neural mechanisms underlying SCI pain and will identify ovarian hormones as targets that can readily be modulated to prevent and treat SCI-related pain. This is very important, since current drug therapies and surgical interventions are inadequate.