Sex differences in allodynia: a complex interaction between 17beta-oestradiol and the innate immune system.

Abstract

Chronic pain is a debilitating and costly disease that is well known to preferentially affect women, particularly in their child bearing years. In spite of the obvious differences in pathophysiology between the sexes, the underlying mechanisms causing this sex difference in chronic pain have not yet been determined. Contributing to this gap in knowledge is the unrelenting use of preclinical animal pain models along with pain behavioural assessment techniques, which fail to best replicate the clinical pain experience. This translatability issue, along with the continued preferential use of male subjects in preclinical chronic pain investigations has meant that researchers have not yet uncovered what contributes to this sex difference in pain sensitivity, resulting in half the population (females) being inadequately treated for their pain. Among the numerous mechanisms that have been proposed to underlie this sex difference in chronic pain are both the gonadal hormones, particularly 17β-oestradiol, along with the innate immune system. Although seperately known to play a role in chronic pain, prior to this PhD project, the relationship between these two systems had not be investigated in this debilitating condition. Recent evidence however has revealed not only the presence of oestrogen receptors on the key neuroimmune cells in pain responsive regions of the CNS, but also the exaggerated production of pain producing pro-inflammatory mediators in response to their activation. Given therefore that an association between these two pain-producing systems does exist, this PhD project investigated the relationship between 17β-oestradiol and the innate immue system in exaggerated female chronic pain. Furthermore, based on the significant and reported translatability issues relating to preclinical pain studies in light of the currently available chronic pain experimental models and assessment techniques, this study further examined this relatinship for the first time using novel translatable preclinical methodologies. Through a series of key in vitro and in vivo studies our findings not only present and validate a novel preclinical chronic pain model and behavioural assessment technique that better produces and examines a preclincal neuropathy, but our findings also substantiate previous work demonstrating a significant role of 17β-oestradiol in chronic pain. Importantly this PhD project reveals for the first time not only the capability of the oestrogens to directly bind to key innate immune signalling receptors involved in chronic pain, but that 17β-oestradiol priming of CNS innate immune cells via such direct binding is in part responsible for the exaggerated female pain phenotype. Overall, the findings of this body of work highlight a fundamental difference in chronic pain pathophysiology between the sexes and further emphasize the importance of treating chronic pain in women during their reproductive years differently from prepubesent female, postmenopausal and male chronic pain sufferers.