Spinal prostaglandin E receptors of the EP2 subtype and the glycine receptor alpha3 subunit, which mediate central inflammatory hyperalgesia, do not contribute to pain after peripheral nerve injury or formalin injection.

Inflammation, peripheral nerve injury and chemical irritants can cause central sensitization in pain pathways. Prostaglandins produced in the CNS induce central sensitization during inflammation mainly by relieving nociceptive neurons from glycinergic inhibition. We have recently identified spinal prostaglandin E receptors of the EP2 subtype (EP2 receptors) and the glycine receptor alpha3 subunit (GlyR alpha3) as signal transduction elements involved in the generation of central inflammatory hyperalgesia. It is however still unknown to what extent inhibition of glycine receptors by PGE2 contributes to neuropathic or chemically induced pain. To address this question, we have analyzed mice deficient in the EP2 receptor (EP2-/- mice) or in the GlyR alpha3 subunit (GlyR alpha3-/- mice) using the chronic constriction injury (CCI) model of neuropathic pain and the formalin test. We found that EP2-/- mice and GlyR alpha3-/- mice develop thermal and mechanical hyperalgesia in the CCI model indistinguishable from that seen in wild-type mice. In the formalin test, EP2-/- mice, but not GlyR alpha3-/- mice, exhibited reduced nocifensive behavior. The lack of a phenotype in GlyR alpha3-/- mice together with the absence of a facilitating effect of intrathecal PGE2 on formalin-induced nociception in wild-type mice suggests that peripheral rather than spinal EP2 receptors are involved. These results indicate that inhibition of glycinergic neurotransmission by EP2 receptor activation does not contribute to pain following peripheral nerve injury or chemical irritation with formalin. Our results thus provide further evidence that inflammatory hyperalgesia and neuropathic pain involve different mechanisms of central sensitization.