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  • We continued to investigate the contribution of

    2020-02-26

    We continued to investigate the contribution of the EP1 hmg-coa reductase inhibitors to nociceptive sensitization by utilizing its natural ligand PGE and tested the effect of local subcutaneous injection of PGE (5nmol in 5μl) into one hindpaw on mechanical and heat pain thresholds. Wild-type mice displayed maximum sensitization to mechanical stimuli 30min after injection of PGE (A, baseline: 3.0±0.1g, sensitized: 1.5±0.2g, mean±SEM). This sensitization was indistinguishable from that of EP1 mice (baseline: 2.8±0.1g, sensitized: 1.4±0.2g, mean±SEM). PGE also resulted in a strong heat sensitization in wild-type mice that reached its maximum 30min after injection (B, baseline: 17.1±1.0s, sensitized: 1.8±0.3s, mean±SEM). However, as reported previously, EP1 mice were significantly less sensitized (baseline: 16.2±1.1s, sensitized: 7.7±1.3s, mean±SEM), while EP2 mice behaved similar to wild-type mice (baseline: 15.9±1.0s, sensitized: 1.2±0.2s, mean±SEM). These data confirm the role of EP1 mediated heat sensitization after local peripheral PGE injection . To investigate the relevance of EP1 receptors in central (spinal) pain sensitization, mice were injected with PGE (0.4nmol in 4μl) directly into the subarachnoid space of the spinal canal, i.e., intrathecally. Intrathecal PGE injection in wild-type mice led to strong mechanical sensitization (A, baseline: 3.2±0.1g, sensitized: 1.5±0.2g, mean±SEM). This sensitization was the same in EP1 animals (baseline: 3.1±0.1g, sensitized: 1.5±0.3g, mean±SEM). However, as previously reported , EP2 animals did not show any sensitization by intrathecally injected PGE (baseline: 3.2±0.1g, sensitized: 3.1±0.1g, mean±SEM), pointing to the central role of EP2 in mechanical sensitization. These results suggest that EP1 receptors in the CNS are not involved in mechanical inflammatory pain sensitization in the mouse. Injection of PGE into the spinal canal of wild-type animals also resulted in heat sensitization (B, baseline: 16.5±0.6s, sensitized: 11.3±0.9s, mean±SEM). In EP1 mice this sensitization was slightly less compared to wild-type mice (baseline: 17.5±0.6s, sensitized: 14.4±0.8s, mean±SEM), but this difference did not reach statistical significance (=0.29, unpaired Student -test). Finally, by injecting zymosan A into the hindpaw the contribution of EP1 to pain sensitization was studied in a model that resembles a more complex natural inflammation (). This was particularly important as the expression of EP receptors might change during inflammation. In wild-type mice, zymosan A caused local paw swelling and led to strong mechanical and thermal sensitization. EP1 mice showed virtually identically responses throughout the time course of the experiment. Because at the dose employed, zymosan A-induced pain sensitization is mainly due to sensitization induced by spinally produced PGE , the absence of a phenotype in this test is consistent with only a minor contribution of EP1 receptors to spinal pain sensitization. Among the four PGE receptors, the EP1 subtype has been proposed as one of the most promising targets against inflammatory hyperalgesia. Early work showed that EP1 mice exhibited significantly reduced nocifensive responses to intraperitoneal injection of acetic acid and to 2-phenyl-1,4-benzoquinone (PBQ) , and a tendency to reduced responses in the formalin test , . Subsequent development of EP1 receptor antagonists proved analgesic activity in a variety of pain models. One of the first specific EP1 receptor antagonists that became available was ONO-8711. This compound reduced mechanical hyperalgesia in nerve injured rats after systemic administration , in rats after intrathecal injection, in the carrageenan model , in an incision model of postoperative pain , or when intrathecally co-injected together with PGE . The more specific ONO-8713 has been reported to reverse thermal hyperalgesia in mice when co-injected peripherally together with PGE . However, further data on ONO-8713 in other pain models is not available. Other EP1 receptor antagonists more recently developed by GlaxoSmithKline showed analgesic activity after systemic administration in a sub-chronic model of knee joint arthritis , . Although these studies provide significant evidence for an analgesic action of EP1 receptor antagonists, a systematic analysis of the contribution of peripheral versus central sites and on the relevance of EP1 receptors for heat and mechanical sensitization is largely lacking. This may still be clinically relevant as a significant contribution of central EP1 receptors would prompt for antagonists being able to cross the blood brain barrier, and because chronic pain patients appear to suffer more from mechanical hypersensitivity than from heat hyperalgesia.