Chronic prostaglandin E2 treatment induces the synthesis of the pain-related peptide substance P and calcitonin gene-related peptide in cultured sensory ganglion explants.
Prostaglandin E2 (PGE2) is a well known pain and pro-inflammatory mediator abundantly produced in inflamed tissue. It causes pain by directly exciting nociceptive primary sensory neurons (nociceptors) and indirectly stimulating the release of pain-related peptide substance P (SP) and calcitonin gene-related peptide (CGRP). In an ex vivo culture of sensory ganglion explants, we tested the hypothesis that PGE2 could induce the synthesis of SP and CGRP in nociceptors. A stabilized PGE2 analog, 16,16-dimethyl PGE2, in a concentration- and time-dependent manner, significantly increased mRNA and peptide levels of SP and CGRP. The agonists of EP1 and EP4 receptors also significantly increased SP and CGRP levels. Moreover, 16,16-dimethyl PGE2-induced SP and CGRP were blocked by EP1 and EP4 antagonists as well as the inhibitors of both protein kinase A and protein kinase C. Nerve growth factor was partially involved in PGE2-induced SP and CGRP synthesis. Taken together, these results indicate that PGE2 contributes to the synthesis of SP and CGRP in nociceptors, an event mediated by EP1 and EP4 receptors, nerve growth factor and protein kinase A and protein kinase C signalling pathways. We thus conclude that facilitating the synthesis of pain-related peptides in nociceptors is a novel mechanism underlying the role of PGE2 in nociception and chronic pain states.
Ma
Weiya
W
Douglas Mental Health University Institute, McGill University, Montreal, Quebec, Canada. weiya.ma@douglas.mcgill.ca
D015064:16,16-Dimethylprostaglandin E2 / Q000494:pharmacology*; D000818:Animals; D000897:Anti-Ulcer Agents / Q000494:pharmacology*; D015740:Calcitonin Gene-Related Peptide / Q000235:genetics / Q000378:metabolism*; D012531:Dibenz(b,f)(1,4)oxazepine-10(11H)-carboxylic acid, 8-chloro-, 2-acetylhydrazide / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005727:Ganglia, Spinal / Q000187:drug effects*; D005786:Gene Expression Regulation / Q000187:drug effects; D008297:Male; D020932:Nerve Growth Factor / Q000378:metabolism; D009924:Organ Culture Techniques; D011448:Prostaglandin Antagonists / Q000494:pharmacology; D011465:Prostaglandins, Synthetic / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018078:Receptors, Prostaglandin E / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013373:Substance P / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors
D000897:Anti-Ulcer Agents; D004791:Enzyme Inhibitors; D011448:Prostaglandin Antagonists; D011465:Prostaglandins, Synthetic; D012333:RNA, Messenger; D018078:Receptors, Prostaglandin E; D012531:Dibenz(b,f)(1,4)oxazepine-10(11H)-carboxylic acid, 8-chloro-, 2-acetylhydrazide; D013373:Substance P; D020932:Nerve Growth Factor; D015740:Calcitonin Gene-Related Peptide; D015064:16,16-Dimethylprostaglandin E2