# The Role of Testosterone on Mediating Sex and Gender Influences on Chronic Orofacial Pain Conditions

> **NIH NIH R01** · UNIVERSITY OF MARYLAND BALTIMORE · 2024 · $461,997

## Abstract

ABSTRACT AND PROJECT SUMMARY
Many chronic pain conditions that affect craniofacial regions, such as temporomandibular disorders (TMD),
disproportionately affect females. A growing number of studies show strong evidence that sex-related differences
in conditioned pain modulation (CPM), a psychophysical index of endogenous pain inhibition, is one mechanism
that predisposes women to an increased risk of chronic pain conditions. However, the central mechanisms
underlying gender differences in CPM, as well as causal links between dysfunctional CPM and chronic orofacial
pain conditions, are largely unknown. Our prior work has shown that there are sex differences in descending
noxious inhibitory control (DNIC), a measure that is similar to CPM in preclinical settings, and that DNIC is
modulated in a testosterone (TS)-dependent manner. The efficiency of DNIC was stronger in males compared
to females. A pharmacological blockade of androgen receptors attenuated DNIC in males, and TS replacement
enhanced DNIC in female rats. We also provided compelling evidence that the efficient DNIC in males is
associated with a stronger resting functional connectivity between the rostral anterior cingulate cortex (rACC)
and the periaqueductal gray (PAG). These observations provide a strong rationale for investigating the impact
of TS on central pain modulation, and they also have significant clinical implications for pain management for
both transgender and cisgender individuals undergoing hormone therapy. In this project, we will investigate the
role of TS in maintaining efficient DNIC, as well as the mechanistic links between dysfunctional DNIC, TMD-like
pain, and TMD-related comorbid pain conditions. Specifically, we hypothesize that the rACC to PAG circuit
mediates sex differences in DNIC efficiency in a TS-dependent manner and that strengthening DNIC effectively
attenuates TMD-related primary and comorbid pain responses. In specific aim (SA) 1, we will determine the role
of the rACC to PAG circuit in DNIC efficiency using a behavioral paradigm and chemogenetics, which will
experimentally manipulate the strength of the circuit with and without anti-androgen treatment in males and with
and without TS treatment in females. In SA2, we will investigate the relationship between DNIC and TMD-like
pain responses. We will conduct a concurrent functional magnetic resonance imaging (fMRI) to assess pain-
induced changes in brain networks and confirm that both TS treatment and strengthening the rACC to PAG
circuit rectify the pain-induced changes in the brain networks in male and female rats. In SA3, we will determine
whether chemogenetically activating DNIC leads to a reduction in TMD-related comorbid pain responses and
whether TS treatment further enhances the chemogenetic effects. The project will significantly improve our
knowledge of the impact of sex on CNS pain modulation, which should have broad translational implications for
the development of customized therapeutic st...

## Key facts

- **NIH application ID:** 10931459
- **Project number:** 5R01DE032225-02
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** Joyce Teixeira Da Silva
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $461,997
- **Award type:** 5
- **Project period:** 2023-09-19 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10931459

## Citation

> US National Institutes of Health, RePORTER application 10931459, The Role of Testosterone on Mediating Sex and Gender Influences on Chronic Orofacial Pain Conditions (5R01DE032225-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10931459. Licensed CC0.

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