Sex differences and the effects of stress on neuroanatomical structures involved in modulating inflammatory pain

Approximately 1 in 5 people suffer from pain worldwide, and women experience more recurrent, severe, and longer-lasting pain. Pain conditions more prevalent in women include migraine, fibromyalgia, irritable bowel syndrome, and temporomandibular joint disorder. Stress can influence pain, and females are more susceptible to stress-exacerbated orofacial pain. As preclinical studies have largely been conducted in males, the mechanisms underlying the effects of stress on pain in females are understudied. Orofacial pain is relayed by sensory neurons in the trigeminal ganglia (TG) that synapse in the brainstem trigeminal nuclear complex (TnC). Ascending pain pathways relay pain signals to the cortex and can initiate descending pain modulation via emotive nuclei in the amygdala and hypothalamus that project to the periaqueductal gray. Our overarching hypothesis is that stress exacerbates orofacial pain to a greater degree in female rats, and there are sex differences in the trigeminal neurocircuitry that transmit somatosensory information to the brain. We utilized behavioral, neuroanatomical, pharmacological, and transcriptomic approaches to investigate sex differences in the effects of stress in a rat model of orofacial pain. We report that stress exacerbates orofacial pain to a greater degree in female rats. Neuroanatomical analyses of the TG and TnC implicate a sex-specific pain mechanism whereby females have dampened GABAergic neurotransmission during stress-exacerbated orofacial pain. In support, pain behaviors were reduced by treatment with a GABAB receptor agonist. Further, when we explored the pain-modulatory projections of the amygdala and hypothalamus to the periaqueductal gray, we uncovered sex differences in their organization and activation by pain, supporting a sexually dimorphic role of emotive brain areas in modulating pain. Overall, our data indicate that stress differentially alters sensory neuron input to the brainstem and is subject to sex-specific descending modulation from emotive centers in the brain. We postulate that women experiencing stress-exacerbated orofacial pain would benefit from a pain management regimen that includes a pharmacological intervention to boost GABA signaling concomitant with interventions that manage stress. Lastly, our transcriptomics data may indicate novel pain therapeutic targets related to the extracellular matrix, which may contribute to the effects of stress on pain chronification in the trigeminal system.