Background & Aims

Individuals experiencing orofacial pain frequently exhibit gender disparities, with a higher prevalence observed in women. Despite this, the mechanisms underlying orofacial pain conditions and their sexual dimorphism remain poorly understood. Given the evident variations in anatomical structures, gonadal hormones, and immune responses between males and females, it is hypothesized that these factors contribute to the sexual dimorphism observed in orofacial pain. In using animal models to investigate the pathophysiology of orofacial pain and the efficacy of disease-modifying drugs, appropriate use and representation of female as well male animals is important. The aim of this study was to examine whether there is sexual dimorphism in the nociceptive responses of mice and rats in experimental models of acute and chronic orofacial nociception.

Methods

Adult Swiss mice (20 – 30 g) and Wistar rats (200-250 g), both sexes, were used. Cutaneous orofacial nociception was induced in male and female mice (n=6/group) by the injection (20 ?L) of cinnamaldehyde (0.66 ?M) or capsaicin (2.5 µg) into the right upper lip and nociception was quantified by the time the animal spent rubbing the injection site. Temporomandibular joint (TMJ) nociception was induced in male and female rats (n=6/group) by the injection (50 ?L) of 2.0% formalin into the left TMJ. Nociception was quantified as the number of asymmetric rubbings of the orofacial region and head jerking and chewing-like movements. Chronic orofacial nociception was induced in male and female mice by infraorbital nerve transection injury (IONX). The mechanical sensitivity of the facial whisker skin was evaluated using Von Frey test. Naïve groups (n=6/each) were included in all tests. Sham groups (n=6/each) were included in the TMJ and IONX tests. Blind design was used.

Results

The application of capsaicin and cinnamaldehyde produced an increase (ANOVA followed by Tukey; p<0.0001) in nociceptive behaviour in female and male animals in relation to the respective naïve groups. However, male animals spent more time rubbing the orofacial region than female animals (p<0.0001 – capsaicin and p<0.01 - cinnamaldehyde). Male and female animals that received formalin into the TMJ showed nociceptive behaviour (ANOVA followed by Tukey; p<0.0001) in relation to the respective naïve and sham groups, but the number of nociceptive behaviours was greater in male animals (p<0.05) than in female animals. Facial mechanical sensitivity was induced and maintained for 21 days (Two-way ANOVA followed by Bonferroni; p<0.0001) after IONX in male and female mice, but there was no difference between the sensitivity of male and female animals (p<0.05).

Conclusions

Male animals were more sensitive than females to nociceptive stimuli produced by capsaicin, cinnamaldehyde and formalin, but not to that produced by transection of the infraorbital nerve. Overall, these findings emphasize the need to incorporate both sexes in future orofacial pain studies in order to obtain a better understanding of the mechanisms that drive orofacial pain states and to develop improved diagnostic and therapeutic options for orofacial pain patients.

References

Häggman-Henrikson B, Liv P, Ilgunas A, Visscher CM, Lobbezoo F, Durham J, Lövgren A. Increasing gender differences in the prevalence and chronification of orofacial pain in the population. Pain. 2020 Aug;161(8):1768-1775. doi: 10.1097/j.pain.0000000000001872.
Ivan S, Daniela O, Jaroslava BD. Sex differences matter: Males and females are equal but not the same. Physiol Behav. 2023 Feb 1;259:114038. doi: 10.1016/j.physbeh.2022.114038.
Liu S, Kramer P, Tao F. Editorial: Mechanisms of Orofacial Pain and Sex Differences. Front Integr Neurosci. 2021 Mar 10;15:599580. doi: 10.3389/fnint.2021.599580.
Sessle BJ. Chronic Orofacial Pain: Models, Mechanisms, and Genetic and Related Environmental Influences. Int. J. Mol. Sci. 2021, 22, 7112. https://doi.org/10.3390/ijms22137112

Presenting Author

Adriana Rolim Campos

Poster Authors

Adriana Barros

DSc

University of Fortaleza

Lead Author

E-mail

Sacha Aubrey Santos RPh

Universidade de Fortaleza

Lead Author

E-mail

Marina Damasceno PharmD

Universidade de Fortaleza

Lead Author

E-mail

Gerlânia Leite PhD

Universidade Federal do Cariri

Lead Author

E-mail

Francisco Ernani Magalhães PhD

Universidade Estadual do Ceará

Lead Author

E-mail

Barry Sessle PhD

University of Toronto

Lead Author

E-mail

Topics

  • Gender/Sex Differences