The Sex-Specific Role of Prolactin in Apical Periodontitis Pain - Abstract
In the United States alone, ~$8 billion is spent each year to perform over 15 million root canal procedures to
treat and prevent the development of apical periodontitis (AP). AP is a painful disease in which the tissues
surrounding the tooth become inflamed due to dental pulp infection or physical trauma. This inflammation is
characterized by decreased mechanical pain thresholds, or mechanical allodynia. While root canal treatments
relieve AP pain in most cases, ~7-12% of patients will continue to experience endodontic pain >6 months after
the procedure, with females being four times more likely than males to experience post-operative chronic pain.
Current pharmacological treatment options pose serious risks such as addiction, unwanted side effects, and
overdose. Therefore, the yet unknown mechanisms that put females at risk for greater pain due to AP need to
be elucidated to allow for potential new therapies that directly address this prevalent clinical presentation.
Using preclinical models of AP, we discovered that prolactin is highly expressed within the AP site in female
mice, not male mice. Because of its emerging sex-specific pro-nociceptive effects, prolactin signaling could be
a promising target for treating female AP patients. Thus, we hypothesize that increased prolactin levels
mediate a sexually dimorphic AP-mediated mechanical allodynia with greater allodynia in female compared to
male mice. To address this central hypothesis, Aim 1 will test the hypothesis that cell-specific prolactin and
prolactin receptor (PRLR) expression is increased in females in a mouse model of AP. Here, we will induce AP
by creating a pulp exposure and allow for infection in the maxillary first molar of male and female mice. The
infection will manifest over the course of 3, 7, 14, and 21 days, at which point, we will determine the
percentage of prolactin- and prolactin receptor-expression cells in the periapical lesion. Upon completion of this
aim, we expect that female mice will exhibit greater levels of prolactin in the periapical lesion and increased
PRLR expression on trigeminal afferents and in the trigeminal ganglia. Moreover, Aim 2 will test the hypothesis
that prolactin increases apical periodontitis-induced mechanical allodynia in a sexually dimorphic manner. After
pulp exposure, mechanical allodynia will be assessed using von Frey filaments on the vibrissal pad. We will
use global; nociceptor-specific; and immune cell specific PRLR knockout transgenic mice to assess the overall
contribution of prolactin to nociceptor-sensitization. Additionally, we will quantify immune cell populations within
the lesion using RNAscope to further understand the role of prolactin in periapical inflammation contributing to
nociceptor-sensitization. With the completion of these experiments, we will demonstrate the sex-specific role of
prolactin in AP-induced mechanical allodynia. Examining the role of prolactin provides a new target for
developing therapeutics to address the lack of effective AP treatments. It is crucial to understand how prolactin
sex-specifically impacts regulation of AP pain to develop new non-opioid approaches to treat the millions of
patients suffering from AP, and this project will serve to enhance my training as an early career scientist.
