UC San Diego

Chronic pain manifests as a debilitating pathological state that affects up to 10% of the global population. Previous investigations revealed a disproportionate distribution of pain experience between sexes with females reporting a higher prevalence of chronic pain compared to males. The physiological mechanisms underlying the sex difference in pain remains unclear.

The ventrolateral periaqueductal gray is a midbrain region notably involved in modulating opioid activity and nociception, a measurable alternative of pain. Recently, the neuropeptide kisspeptin and its receptor, Kiss1R, known for their role in the reproductive system, have been generally identified in the periaqueductal gray. Hypothalamic kisspeptin expression is sexually dimorphic and directly controlled by sex steroids. Kisspeptin and Kiss1R have been recently attributed to mediate nociceptive experience. Limited research has investigated their role in the ventrolateral periaqueductal gray and contribution to sex differences in nociception.

This study aimed to explore the relationship of sex steroids, kisspeptin, and Kiss1R in the periaqueductal gray to identify the physiological components underlying the sex difference in nociception. We identified the presence of kisspeptin neurons in the ventrolateral periaqueductal gray with no sex difference in quantity and further revealed the presence of Kiss1R on GABAergic neurons in the ventrolateral periaqueductal gray. Additionally, we discovered a sexual dimorphic pattern of Kiss1 and Kiss1r mRNA expression in the ventrolateral periaqueductal gray (vlPAG), with higher levels in female mice that are not regulated by sex steroids. Our current results suggest that known inducers of vlPAG neuroplasticity, chronic pain and chronic opioid treatment, upregulate and downregulate PAG Kiss1 and Kiss1r. Kisspeptin levels in female mice remains higher than males regardless of these conditions.

Our findings establish the presence, sexual dimorphism, and modulation of kisspeptin and Kiss1R in the ventrolateral periaqueductal gray. We hypothesize that these populations may be contributing to sex differences seen in nociception. Our work further characterizes the regulation and profile of kisspeptin and Kiss1R in the ventrolateral periaqueductal gray that will aid in conducting further studies examining the sex differences of transcriptional mechanisms and neuronal pathways involved in nociception