Abstract Body: The cannabinoid receptors CB1R and CB2R are involved in blood pressure (BP) regulation and CB1R is implicated in the incidence of hypertension. CB1R is highly expressed in the brain but both receptors are also expressed in the heart. Prior research has demonstrated that CB1R mediates significant cardiovascular responses, including elevated BP, heightened plasma norepinephrine levels, and increased sympathetic nerve activity. Furthermore, the activation of the kinin B1 receptor (B1R) mediates similar effects when studied independently. However, the role of B1R in CB1R-mediated BP regulation and the associated signaling mechanisms remain unknown. In this study, we tested the hypothesis that B1R plays a pivotal role in CB1R-mediated pressor response, oxidative stress and neuroinflammation. To test this, we used both in vivo mouse models and in vitro primary hypothalamic neurons. Male C57BL/6NJ wild-type (WT) and B1R knockout mice (B1RKO) underwent surgical carotid artery and jugular vein catheterization to measure BP in conscious state. Following stabilization of BP for at least 90 minutes, the CB1R agonist WIN55,212-2 (300 ug/kg; i.v., WIN) or its vehicle was administered, and recordings continued for 45 minutes. WIN increased BP in WT mice (25±7 mmHg vs baseline), but this effect was blunted in B1RKO mice (n=3, p<0.05). Moreover, administration of WIN led to an augmentation of CB1R expression in the paraventricular nucleus of WT mice, but not in B1RKO mice, thereby indicating the involvement of B1R in CB1R signaling (p<0.05, n=3 mice/group). WT, but not B1RKO, mice treated with WIN displayed a significant increase in oxidative stress levels (p<0.05, n=3 mice/group), as indicated by dihydroethidium staining. To further confirm the role of B1R blockade on CB1R signaling, we cultured primary hypothalamic neurons, as neurons express the highest levels of CB1R in the brain. Neurons were stimulated with WIN (1 uM) both with and without a B1R selective antagonist (SSR240612, 10uM). The results indicated that WIN incubation for 24 hours increased CB1R expression, inflammation, and oxidative stress compared to vehicle treated, and these responses were abrogated by prior B1R blockade (p<0.05, n=5/group), consistent with the in vivo observations. These data provide novel evidence that B1R is implicated in CB1R-mediated proinflammatory responses and serves as a potential therapeutic target to reduce CB1R induced effects.