| Abstract No.: | A-D1133 |
| Country: | Canada |
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| Title: | STIMULATING THE SYNTHESIS OF PAIN-RELATED PEPTIDE SUBSTANCE P AND CALCITONIN GENE-RELATED PEPTIDE IN NOCICEPTORS IS A NOVEL MECHANISM UNDERLYING THE ROLE OF PROSTAGLANDIN E2 IN NOCICEPTION |
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| Authors/Affiliations: | 1 Weiya Ma*; 1 Wataru Inoue; 1 Giamal Luheshi; 1 Remi Quirion;
1 Douglas Mental Health University Institute, McGill University; Montreal, QC, Canada
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| Content: | Prostaglandin E2 (PGE2) is a well established pain mediator. It plays a role in nociception through directly exciting nociceptive primary sensory neurons (nociceptors) and indirectly stimulating the release of pain-related neuropeptide including substance P (SP) and calcitonin gene-related peptide (CGRP) from nociceptors. We have shown before that peripheral administration of the inhibitor of cyclooxygenases 2 (COX2), an enzyme involved in the synthesis of PGE2, dramatically reduced the levels of SP and CGRP in the dorsal root ganglion (DRG) and in the superficial dorsal horn (Ma et al., Soc.Neurosci.Abstr., 286.10, 2007). This finding suggests that peripherally derived PGE2 is likely involved in the synthesis of pain-related peptides in nociceptors. In the present study, we tested this hypothesis and found that exposure of cultured DRG explants to 16,16 dimethyl PGE2 (dmPGE2), a stabilized PGE2 analog, dose- and time-dependently increases the contents of SP and CGRP in DRG explants. The levels of SP and CGRP reached the peak by 3 and 72 hours, respectively, after dmPGE2 treatment. We subsequently investigated the subtypes of PGE2 EP receptors involved in dmPGE2 induced SP and CGRP in DRG neurons. We found that PGE2 EP1 and EP4 receptors were extensively co-localized with SP and CGRP while EP2 and EP3 were rarely co-expressed with the two peptides in small to medium size DRG neurons. Although the agonists of both EP1 and EP4 receptors were able to increase the levels of SP and CGRP in cultured DRG explants, EP1 agonist 17-phenyl trinor PGE2 and EP4 agonist 1-hydroxy PGE1 were predominant respectively in the induction of SP and CGRP. The inducing effects of EP1 and EP4 agonists on SP and CGRP were blocked by pre-and co-treatment with EP1 antagonist SC19220 and EP4 antagonist AH23848, respectively. We next examined the signalling events involved in the induction of SP and CGRP by EP1 and EP4 agonists. We found that the inhibitors of both protein kinase A (PKA) and PKC were able to block the effects of EP1 and EP4 agonists. Taken together, our data further supports the hypothesis that PGE2 is involved in the synthesis of pain-related peptide SP and CGRP in nociceptive DRG neurons. EP1 and EP4 receptors as well as PKA and PKC signalling pathways likely mediate PGE2 induced SP and CGRP. Thus, we concluded that facilitating the synthesis of pain-related peptides in nociceptors is a novel mechanism underlying the role of PGE2 in nociception. (Supported by the Canadian Institutes of Health Research) |
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