Patients with osteoarthritis experience pain when moving or, sometimes, touching the affected joints. Raouf et al. identified proteins that bound to a toxin that inhibits mechanically induced pain, including the membrane-binding protein annexin A6. Mice lacking annexin A6 were more sensitive to mechanically induced pain, whereas overexpression of annexin A6 in sensory neurons reduced pain in a mouse model of osteoarthritis. These results suggest that strategies that increase the abundance of annexin A6 could alleviate the chronic pain of osteoarthritis.Mechanically activated, slowly adapting currents in sensory neurons have been linked to noxious mechanosensation. The conotoxin NMB-1 (noxious mechanosensation blocker-1) blocks such currents and inhibits mechanical pain. Using a biotinylated form of NMB-1 in mass spectrometry analysis, we identified 67 binding proteins in sensory neurons and a sensory neuron–derived cell line, of which the top candidate was annexin A6, a membrane-associated calcium-binding protein. Annexin A6–deficient mice showed increased sensitivity to mechanical stimuli. Sensory neurons from these mice showed increased activity of the cation channel Piezo2, which mediates a rapidly adapting mechano-gated current linked to proprioception and touch, and a decrease in mechanically activated, slowly adapting currents. Conversely, overexpression of annexin A6 in sensory neurons inhibited rapidly adapting currents that were partially mediated by Piezo2. Furthermore, overexpression of annexin A6 in sensory neurons attenuated mechanical pain in a mouse model of osteoarthritis, a disease in which mechanically evoked pain is particularly problematic. These data suggest that annexin A6 can be exploited to inhibit chronic mechanical pain.