Neuronal prostaglandin E ₂ receptor subtype EP3 mediates antinociception during inflammation

Abstract

The pain mediator prostaglandin E 2 (PGE 2 ) sensitizes nociceptive pathways through EP2 and EP4 receptors, which are coupled to G s proteins and increase cAMP. However, PGE 2 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 PGE 2 . 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 PGE 2 , 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. mechanical hyperalgesia | sodium currents P rostaglandins regulate immune responses (1), and they are key mediators of pain and other sickness symptoms such as fever, sleepiness, and anorexia (2). In particular, prostaglandin E 2 (PGE 2 ) is a key mediator of pain because it sensitizes peripheral and spinal nociceptive pathways (3-7). Hence the most common pain treatment is the inhibition of prostaglandin synthesis by cyclooxygenase inhibitors. PGE 2 activates neuronal EP1-4 receptors (8). In this context, it is noteworthy that different EP receptors are coupled to different, partly even opposing intracellular signaling pathways. EP2 and EP4 receptors, which sensitize neurons (9-11), are coupled to G s proteins and increase cAMP (12, 13). In contrast, the major signaling pathway of the EP3 receptor splice variants uses inhibition of cAMP synthesis via G i proteins (12, 13). The functional significance of such opposite effects raises the intriguing question of whether the G i -protein-coupled EP3 receptor may counteract the EP2 and EP4 receptor-mediated pronociceptive effects of PGE 2 (9). Thus, the role of PGE 2 may not be just pronociceptive as usually assumed but it may be rather more diverse and depend on the biological context, as during inflammation (1). In the present experiments, we addressed the hypothesis that EP3 receptor activation is rather antinociceptive than pronociceptive. We found that the EP3 receptor is heavily expressed in rat sensory dorsal root ganglia (DRG) and spinal cord as well as in peripheral nerves including nerve fibers of osteoarthritic knees of humans. Selective activation of the EP3 receptor did no...

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