Neuronal prostaglandin E2 receptor subtype EP3 mediates antinociception during inflammation.

The paper by Schaible and colleagues is of interest because it proposes a new target in the prostaglandin pathway that is fundamentally different from that of COX-1 or COX-2 inhibitors. Several people have looked at EP1, EP2, EP3, and EP4 agonists and antagonists (for review see Flesch et al., 2013) in the past without convincing evidence of utility against pain targets in man; this paper proposes an EP3 receptor in the brain, spinal cord, and peripheral nerves where EP3 selective agonists (e.g., ONO-AE-248) produce significant analgesic responses that are blocked by selective EP3 antagonists (e.g., ONO-AE3-240). The authors further distinguish this from effects produced by EP2 and EP4 agonists.

It’s clear that Ono Pharmaceutical (Japan) has been thinking about this for a long time. I know of other companies that have been involved with EP agonists in the past; I’m sure that anyone who has been looking at this from afar will now jump in with their own programs.

I read this publication with great interest: The authors elegantly demonstrated that EP2 and EP4 receptors sensitize nociceptive neurons, whereas EP3 receptor activation counteracts pain induced by inflammation. EP2 and EP4 receptors play a role not only in inflammatory joint pain, as described in this paper, but also in joint pathology by stimulating inflammatory pain mediators and promoting cartilage degeneration (Li et al., 2009). In the paper published by Li et al., however, it is not clear whether EP3 receptors are indeed capable of counteracting EP2 and EP4 receptors in joint pathology, and thus it is tempting to conduct studies to see if this is the case. Also, it would be interesting to determine the role of EP receptors in synovial lining cells, which can contribute to joint pathology as well as hypersensitivity in knee joints—are EP2 and EP4 pro-inflammatory and capable of being counteracted by the EP3 agonist? The outcome may not be so simple, but I look forward to seeing the results.

The animal models in this pain study make use of either the acute or chronic inflammatory (rheumatoid arthritis) pain model. Although osteoarthritis could be characterized by inflammation, it would be very mild, and pain mechanisms may differ. Exploring pharmacological efficacy of the EP3 agonist using an experimental osteoarthritis animal model would be worthwhile.