Chronic pain is the nation’s leading public health crisis, affecting over 20% of the U.S. population and exhibiting significant sex-dependent differences in prevalence, presentation, and severity. It reduces both the length and quality of life, imposing substantial physical, emotional, mental, and economic burdens. Current management strategies rely heavily on pharmaceuticals; however, these treatments are often limited in efficacy and can pose significant risks for both sexes (e.g., the opioid epidemic), with unequal outcomes. Therefore, a deeper fundamental understanding of sex-dependent differences in clinical presentation and therapeutic response, along with the development of improved treatment strategies, is urgently needed. To address this gap, researchers are increasingly adopting mechanism-agnostic, phenotype-driven approaches that better capture complex biological variability. In this context, developing biologically relevant models that incorporate sex-specific differences is critical for enabling more effective and targeted compound screening. Here, we present preliminary data on the development of a sex- and hormone-dependent phenotypic inflammatory nociception model using 2D co-cultures of human induced pluripotent stem cell derived sensory neurons (hiPSC-SNs) and glia on microelectrode arrays (MEAs). Female- and male-derived co-cultures are treated with estradiol and progesterone, respectively, and subsequently used to evaluate two Nav1.8 channel inhibitor compounds. Spontaneous and evoked electrophysiological activities are assessed and integrated with RNA-sequencing data to characterize sex- and hormone-dependent differences in nociceptive signaling.