The pain mediator prostaglandin E₂ (PGE₂) sensitizes nociceptive pathways through EP2 and EP4 receptors, which are coupled to G_s proteins and increase cAMP. However, PGE₂ also activates EP3 receptors, and the major signaling pathway of the EP3 receptor splice variants uses inhibition of cAMP synthesis via G_i proteins. This opposite effect raises the intriguing question of whether the G_i-protein–coupled EP3 receptor may counteract the EP2 and EP4 receptor-mediated pronociceptive effects of PGE₂. We found extensive localization of the EP3 receptor in primary sensory neurons and the spinal cord. The selective activation of the EP3 receptor at these sites did not sensitize nociceptive neurons in healthy animals. In contrast, it produced profound analgesia and reduced responses of peripheral and spinal nociceptive neurons to noxious stimuli but only when the joint was inflamed. In isolated dorsal root ganglion neurons, EP3 receptor activation counteracted the sensitizing effect of PGE₂, and stimulation of excitatory EP receptors promoted the expression of membrane-associated inhibitory EP3 receptor. We propose, therefore, that the EP3 receptor provides endogenous pain control and that selective activation of EP3 receptors may be a unique approach to reverse inflammatory pain. Importantly, we identified the EP3 receptor in the joint nerves of patients with painful osteoarthritis.