痛觉内源性调控性别差异现象及其中枢机制研究

More recently, sex-associated differences in pain have received much attention from basic researcheres as well as clinical scientists. Our series of studies conducted in humans and animals have provided novel findings showing that the endogenous descending modulation of pain is normally inactive or 'silent', but not tonic, and needs to be triggered by sufficient C-afferent inputs. Most importantly, our studies have demonstrated that the triggering thresholds for descending modulations on pain in subjects of different sexes differ significantly. In contrast to males, femals have lower and higher triggering thresholds for facilitation and inhibition, respectively. These experimental results provide direct novel evidence in interpretion of sex-related diferences in the perception and modulation of pain. According to these initial results, utilizing multi-disciplinary approaches including behavioral, electrophysiological, immunohistochemical and molecular biology methods, from the systemic, cellular, and molecular levels, the current application will explore potential effects of estrogen and androgen upon endogenous descending controls of pain. Based on the throughly investigation on the bidirectional influrence of "Sex hormone←→Pain", the applicants will reveal potential mechanisms associated with neural signal transduction cascades underlying impact of estrogen and androgen levels on the perception and modulation of pain. The results from the current study may also provide new evidence in effectively relief and control of intractable pathological pain.

晚近，痛觉性别差异现象已愈发受到基础和临床科研工作者的重视。课题组前期系列研究创新性指出痛觉内源性调控（易化和抑制）作用并不是紧张性存在，而是需要外周C-纤维的有效传入而激活。更为重要的是，不同性别个体表现出不同的内源性痛调控激活阈值。与雄性动物相比，雌性动物具有较低的下行易化作用激活阈值和较高的下行抑制作用激活阈值。上述结果为科学解释痛觉性别差异现象提供了直接证据。本课题将在多方法（动物行为学、电生理、免疫组化、分子生物学等）联合的基础上，从整体、细胞和分子角度等层面上深入探讨和验证雌/雄激素对痛觉内源性下行调控作用的影响。通过细致观察"性激素水平←→疼痛"的双向影响，详细分析雌/雄激素水平高低影响痛感知和调控所涉及的细胞和分子水平神经信号转导机制，为临床缓解和治疗难治性、病理性痛提供科研新资料。

目前已广泛认可并接受痛觉存在性别差异现象。本研究联合行为学、电生理学、免疫组织化学等多学科方法，对伤害性反应/痛觉性别差异现象给予了细致探索。通过紧密围绕课题组创新性提出的丘脑MD（mediodorsal）和VM（ventromedial）核团介导的痛觉内源性特异性双调控作用（易化和抑制）这一关键科学论点，我们深入探索了性别因素对痛觉内源性下行调控作用的可能影响，并揭示了睾酮和雌二醇替代治疗方案的细胞和分子机制。课题组首次报道：雌/雄激素对痛觉内源性下行易化和抑制作用具有双重调控作用。表现为：雌激素减弱下行抑制作用，增强下行易化作用；而雄激素显著加强下行抑制作用，并减弱下行易化作用。同时，不同的神经药理学机制介导上述调控作用。本研究为痛觉性别差异现象提供了新型科研证据，并为由于雌/雄激素水平紊乱所造成的痛觉异常现象提供了治疗新思路。.实验结果如下：1）行为学实验：雌性大鼠去势后，高渗盐肌肉注射诱导的机械性痛敏现象减弱，且热痛反应降低现象增强；补充雌二醇可使机械性痛敏现象增强，热痛反应降低现象减弱；补充睾酮，机械性痛敏现象减弱，热痛反应降低现象增强。2）免疫组化实验：丘脑MD核团-大脑皮层扣带回（Cingulate cortex）-中脑导水管灰质背外侧区（dl PAG）-背柱（DF）参与下行易化调控；丘脑VM核团-大脑皮层岛叶（Insular cortex）-中脑导水管灰质腹外侧区（vl PAG）-背外侧索（DLF）参与下行抑制作用。3）神经药理学机制：丘脑Opioid不同受体参与上述调控作用，通过5-HT能和NA能下行通路影响脊髓水平伤害性反应。4）临床治疗学：温针和右美托咪定在不激活下行易化作用的前提下，可通过单独激活下行抑制系统达到镇痛作用。雌/雄激素水平对“超前镇痛”作用产生显著影响，为临床镇痛提供了新的治疗方案。