Neuronal prostaglandin E₂ receptor subtype EP3 mediates antinociception during inflammation

• Published in: Proceedings of the National Academy of Sciences - PNAS 2013-08, Vol.110 (33), p.13648-13653
• Main Authors: Natura, Gabriel, Bär, Karl-Jürgen, Eitner, Annett, Boettger, Michael K., Richter, Frank, Hensellek, Susanne, Ebersberger, Andrea, Leuchtweis, Johannes, Maruyama, Takayuki, Hofmann, Gunther Olaf, Halbhuber, Karl-Jürgen, Schaible, Hans-Georg
• Format: Article
• Language: English
• Subjects: Agonists; Analysis of Variance; Animals; Biological and medical sciences; Biological Sciences; DNA Primers - genetics; Fundamental and applied biological sciences. Psychology; Humans; Immunohistochemistry; Inflammation; Inflammation - physiopathology; Joints; Joints - physiopathology; Knee joint; Medical sciences; Nerves; Nervous system (semeiology, syndromes); Nervous system as a whole; Neurology; Neurons; Nociception - physiology; Nociceptors - metabolism; Osteoarthritis - physiopathology; Pain; Patch-Clamp Techniques; Polymerase Chain Reaction; Polymorphism, Restriction Fragment Length; Prostaglandins; Rats; Rats, Inbred Lew; Receptors; Receptors, Prostaglandin E, EP3 Subtype - metabolism; Spinal cord; Vertebrates: nervous system and sense organs
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1300820110

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.