Department of Pharmaceutical Sciences, Western University of Health Sciences, Pomona, USA.
Eur J Pain. 2014 Jan;18(1):39-46. doi: 10.1002/j.1532-2149.2013.00346.x. Epub 2013 Jun 10.
Sex differences in pain have been well documented; however, the mechanisms involved remain to be elucidated. The present study examined whether sex differences exist in the functioning of primary afferent fibres by assessing formalin-evoked release of substance P by way of neurokinin 1 receptor (NK1r) internalization. The study also investigated whether the observed effects would be oestradiol-sensitive.
Intact and gonadectomized male and female rats were given intraplantar formalin and then euthanized either 5 or 30 min later, representing phase 1 or 2 of the formalin response, respectively. In a subsequent experiment, ovariectomized females received oestradiol prior to formalin administration. Lastly, formalin-evoked NK1r internalization was assessed across the female oestrous cycle.
Intraplantar formalin evoked significant NK1r internalization, during phase 1 and 2, in both males and females. During phase 1, no differences in NK1r internalization were detected between males or females, regardless of the gonadal status. In contrast, during phase 2, intact females exhibited greater NK1r internalization than intact males. Moreover, ovariectomy reduced NK1r internalization as compared to intact females, whereas castration had no effect as compared to intact males. Oestradiol supplementation in ovariectomized females increased NK1r internalization to levels observed in intact females. Formalin-evoked NK1r internalization did not differ across the oestrous cycle.
These findings suggest that oestradiol mediates sex differences in formalin-evoked substance P release, which may contribute to a differential development of central sensitization and pain behaviours in males and females.
性别与疼痛之间的差异已得到充分证实；然而，相关的作用机制仍有待阐明。本研究通过评估通过神经激肽 1 受体（NK1r）内化的福尔马林诱发的 P 物质释放，检查初级传入纤维功能是否存在性别差异。该研究还调查了观察到的效应是否对雌激素敏感。
给完整和性腺切除的雄性和雌性大鼠注射足底福尔马林，然后分别在 5 或 30 分钟后处死，分别代表福尔马林反应的 1 相和 2 相。在随后的实验中，给去卵巢雌性大鼠在注射福尔马林之前给予雌激素。最后，评估了雌性发情周期中福尔马林诱发的 NK1r 内化。
足底福尔马林诱发 NK1r 内化，在 1 相和 2 相中，雄性和雌性均显著。在 1 相时，无论性腺状态如何，雄性和雌性之间的 NK1r 内化均无差异。相比之下，在 2 相中，完整的雌性比完整的雄性表现出更大的 NK1r 内化。此外，与完整的雌性相比，去卵巢减少了 NK1r 的内化，而与完整的雄性相比，去势则没有影响。在去卵巢雌性大鼠中补充雌激素可将 NK1r 内化增加到与完整雌性相同的水平。福尔马林诱发的 NK1r 内化在发情周期中没有差异。
这些发现表明，雌激素介导了福尔马林诱发的 P 物质释放中的性别差异，这可能导致雄性和雌性中枢敏化和疼痛行为的差异发展。
