Prostatitis accounts for 2 million outpatient visits per year in the United States, including 1% of those to primary care physicians. Chronic prostatitis/Chronic pelvic pain syndrome (CP/CPPS) is clinically characterized by dysuria and pain in the perineum, testes, penis, and suprapubic region. Despite CPPS accounting for 90% of all chronic prostatitis, there is an absence of effective therapies. In animal models, the chronic pelvic pain is shown to be associated with immune dysregulation and the activation of nociceptive pathways in the peripheral and central nervous system. We previously demonstrated that a commensal Staphylococcus epidermidis strain derived from the prostate of a healthy human volunteer could be delivered intraurethrally to rapidly inhibit the pathogenic immune response and lead to a profound amelioration of pelvic pain. In the last period of this grant we isolated, purified, and recapitulated the anti-nociceptive effects using the lipoteichoic acid (SELTA) component of the whole bacteria. We demonstrated immunomodulatory activity through induced expression of checkpoint ligands PD-L1 and PD-L2. In preliminary studies in support of this application, we examined direct effects of SELTA on dorsal root ganglia neurons and identified that SELTA is capable of TLR2 dependent activation of a homeostatic neuronal pathway involved in pain modulation. SELTA treatment was also demonstrated to increase expression of the endogenous opioid pathway in neurons. We therefore hypothesize that SELTA can mediate anti-nociceptive effects by modulation of neuronal excitability through activation of homeostatic inhibitory signaling and induction of endogenous opioid pathways. In this study we will dissect novel mechanisms underlying activation of these anti-nociceptive pathways using a combination of animal models, ex vivo dorsal root ganglia slice recordings and in vitro signaling studies. Proof of concept for SELTA activity will be demonstrated in human dorsal root ganglia. The proposed studies will provide a mechanistic understanding of how SELTA exerts anti-nociceptive activity and will set- the-stage for its development as a novel cutting-edge therapeutic for chronic pelvic pain.