Ischemic insult increases spontaneous and evoked pain-related behaviors, reduces grip strength, and increases mean arterial blood pressure after exercise. A, One day after BAO or PenCON injection with BAO, paw-guarding scores are significantly increased compared with Naive mice; however, selective knockdown of P2Y1 (PenY1+BAO) partially prevents the observed injury-induced changes in guarding. B, Mechanical withdrawal thresholds are also found to be reduced after ischemic injury, but P2Y1 knockdown also partially prevents the development of mechanical hypersensitivity. C, Grip strength was significantly reduced compared with baseline in the BAO and PenCON+BAO groups, but not in the Naive or P2Y1-knockdown mice. D, The BAO and PenCON+BAO groups also showed a significant increase in systemic MBP specifically when low-intensity exercise was combined with the ischemic injury, but this was also prevented by afferent-specific inhibition of P2Y1. Two-way repeated-measures ANOVA with Bonferroni's post hoc, *p < 0.05 vs 1 d BAO, **p < 0.01 vs baseline and 1 d Naive.