Sex differences in estradiol secretion by trigeminal brainstem neurons

David A Bereiter, Randall Thompson, Md. M Rahman

Research output: Contribution to journalArticlepeer-review

2 Scopus citations


Estrogen status is a significant risk factor in the development of temporomandibular joint disorders (TMD). Classically, estrogen status is thought to derive mainly from ovarian sources; however, it is well known that estradiol (E2) also is synthesized by neurons in the brain. This study tested the hypothesis that E2 is produced by neurons in trigeminal subnucleus caudalis (Vc), the principal site of termination for sensory afferents that supply the temporomandibular joint (TMJ), to modify evoked responses in a model of TMJ nociception in male and female rats. Intra-TMJ injection of the small fiber excitant, allyl isothiocyanate (AIC), increased the levels of E2 collected from microdialysis probes sites at Vc of ovariectomized (OvX) female rats, ipsilateral to the stimulus, whereas males displayed no change. Dialysate levels of E2 collected from probe sites in the contralateral Vc or cerebellum in OvX rats were not affected by TMJ stimulation. Reverse dialysis of anastrozole, an aromatase (ARO) inhibitor, via the probe reduced perfusate levels of E2 in Vc. Systemic administration of letrozole, a non-steroid ARO inhibitor, for 4 days prevented TMJ-evoked increases in masseter muscle electromyography (MMemg) activity. ARO-positive neurons were distributed mainly in superficial laminae (I-III) at Vc and cell counts revealed no significant difference between OvX and male rats. Intra-TMJ injection of AIC revealed similar numbers of ARO/Fos dual-labeled neurons in OvX and male rats. By contrast, the percentage of ARO neurons co-labeled for glutamic acid decarboxylase (GAD), the biosynthetic enzyme for GABA, was greater in OvX (35%) than male rats (14%). Few ARO-positive neurons were co-labeled for estrogen receptor alpha. These data indicate that E2 is secreted continuously by Vc neurons and that acute stimulation of TMJ nociceptors evokes further secretion in a sex-dependent manner. Reduced TMJ-evoked MMemg activity after ARO inhibition suggests that locally produced E2 by Vc neurons acts via paracrine mechanisms to modify TMJ nociception in female rats.

Original languageEnglish (US)
Article number3
JournalFrontiers in Integrative Neuroscience
StatePublished - Feb 2019

Bibliographical note

Funding Information:
This project was supported by a grant from the National Institute of Dental and Craniofacial Research DE026499 (DB).

Funding Information:
The results of this study demonstrated that E2 is produced by ARO neurons in the Vc of male and female rats. E2 is likely secreted tonically since reverse dialysis of an ARO inhibitor through the probe significantly reduced E2 levels in both males and OvX females. By contrast, acute stimulation of TMJ nociceptors by the small fiber excitant, AIC, evoked increases in E2 levels in dialysate samples from probes sites in the Vc in a sex-dependent manner. The TMJ-evoked increase in E2 in OvX females was site-specific since probes placed in the Vc contralateral to the TMJ stimulus or in the cerebellum revealed no change. Evidence that biosynthesis of E2 by ARO serves a functional role in TMJ nociception was supported by the finding that inhibition of ARO greatly reduced TMJ-evoked jaw muscle reflexes. Anatomical analyses revealed a similar number of ARO-positive neurons in superficial laminae of Vc in OvX and male rats and the percentage of dual-labeled ARO/Fos also was similar after TMJ stimulation. However, a greater percentage of ARO neurons in OvX females than males were co-labeled for GAD suggesting that TMJ nociceptors engage trigeminal brainstem circuitry differently in males and females.

Publisher Copyright:
© 2019 Bereiter, Thompson and Rahman.

Copyright 2019 Elsevier B.V., All rights reserved.


  • Animal models
  • Aromatase
  • Nociception
  • Temporomandibular disorders
  • Trigeminal nucleus caudalis

Fingerprint Dive into the research topics of 'Sex differences in estradiol secretion by trigeminal brainstem neurons'. Together they form a unique fingerprint.

Cite this