Molecular mechanisms underlying the actions of arachidonic acid-derived prostaglandins on peripheral nociception - PubMed (original) (raw)
Review
Molecular mechanisms underlying the actions of arachidonic acid-derived prostaglandins on peripheral nociception
Yongwoo Jang et al. J Neuroinflammation. 2020.
Abstract
Arachidonic acid-derived prostaglandins not only contribute to the development of inflammation as intercellular pro-inflammatory mediators, but also promote the excitability of the peripheral somatosensory system, contributing to pain exacerbation. Peripheral tissues undergo many forms of diseases that are frequently accompanied by inflammation. The somatosensory nerves innervating the inflamed areas experience heightened excitability and generate and transmit pain signals. Extensive studies have been carried out to elucidate how prostaglandins play their roles for such signaling at the cellular and molecular levels. Here, we briefly summarize the roles of arachidonic acid-derived prostaglandins, focusing on four prostaglandins and one thromboxane, particularly in terms of their actions on afferent nociceptors. We discuss the biosynthesis of the prostaglandins, their specific action sites, the pathological alteration of the expression levels of related proteins, the neuronal outcomes of receptor stimulation, their correlation with behavioral nociception, and the pharmacological efficacy of their regulators. This overview will help to a better understanding of the pathological roles that prostaglandins play in the somatosensory system and to a finding of critical molecular contributors to normalizing pain.
Keywords: DRG neuron; Inflammation; Pain; Prostaglandin; Signal transduction.
Conflict of interest statement
The authors declare that they have no competing interests.
Figures
Fig. 1
Biosynthetic pathways of arachidonic acid-mediated prostaglandins (PGs). PGH2 is generated from arachidonic acid by enzymatic reactions of COX-1 or COX-2, and is further metabolized into PGE2, PGD2, PGI2, or TXA2 by specific synthases. When dehydrated, PGE2 is converted into PGA2 and PGB2, and PGD2 is converted into PGJ2. PGJ2 can further be isomerized into 15-deoxy-Δ12,14-PGJ2 (15d-PGJ2). TXA2 is rapidly hydrolyzed into TXB2
Fig. 2
Signaling pathways initiated by prostanoids released from peripheral inflammation. a PGE2-induced activation of EP receptors in somatosensory neurons. In somatosensory neurons, the EP1 receptor is associated with the G protein, Gαq and its activation triggers the release of intracellular Ca2+ from the endoplasmic reticulum through inositol 1,4,5-trisphosphate (IP3) production. EP2 and EP4 receptors are coupled with Gαs, which stimulates cyclic adenosine monophosphate (cAMP) production by activating adenylyl cyclase (AC), whereas EP3 receptor-coupled Gαi activation inhibits cAMP production by inhibiting AC. cAMP in turn activates protein kinase A (PKA), causing phosphorylation of various signaling proteins including epsilon type protein kinase C (PKCε). b-d Signaling pathways initiated by the activation of DP, IP, and TP receptors in somatosensory neurons. The DP1-linked Gαs stimulates intracellular cAMP production, whereas DP2-associated Gαi inhibits cAMP production. The counter-action of DP1 and DP2 (b) receptors regulates cAMP accumulation in the cytosolic compartment. The activation of IP (c) or TP receptors (d) recruits Gαs protein, activates AC, and consequently raises the intracellular cAMP level
Fig. 3
Pro-nociceptive effector molecules that contribute to pain exacerbation by PGs in somatosensory neurons. The functions of diverse ion channels, transporters, and metabotropic receptors are altered by the signal transductions described in Fig. 2, eventually promoting the electrical excitability, neurogenic inflammation, and neuritogenesis of somatosensory neurons
Similar articles
- Arachidonic acid pathways in nociception.
Smith HS. Smith HS. J Support Oncol. 2006 Jun;4(6):277-87. J Support Oncol. 2006. PMID: 16805330 Review. - Prostaglandins, arachidonic acid, and inflammation.
Kuehl FA Jr, Egan RW. Kuehl FA Jr, et al. Science. 1980 Nov 28;210(4473):978-84. doi: 10.1126/science.6254151. Science. 1980. PMID: 6254151 Review. - Endocannabinoid and Prostanoid Crosstalk in Pain.
Buisseret B, Alhouayek M, Guillemot-Legris O, Muccioli GG. Buisseret B, et al. Trends Mol Med. 2019 Oct;25(10):882-896. doi: 10.1016/j.molmed.2019.04.009. Epub 2019 May 31. Trends Mol Med. 2019. PMID: 31160168 Review. - Possible anti-inflammatory role of COX-2-derived prostaglandins: implications for inflammation research.
Kapoor M, Shaw O, Appleton I. Kapoor M, et al. Curr Opin Investig Drugs. 2005 May;6(5):461-6. Curr Opin Investig Drugs. 2005. PMID: 15912958 Review. - Prostaglandins and leukotrienes: advances in eicosanoid biology.
Funk CD. Funk CD. Science. 2001 Nov 30;294(5548):1871-5. doi: 10.1126/science.294.5548.1871. Science. 2001. PMID: 11729303 Review.
Cited by
- Oleic acid released by sensory neurons inhibits TRPV1-mediated thermal hypersensitivity via GPR40.
Sendetski M, Wedel S, Furutani K, Hahnefeld L, Angioni C, Heering J, Zimmer B, Pierre S, Banica AM, Scholich K, Tunaru S, Geisslinger G, Ji RR, Sisignano M. Sendetski M, et al. iScience. 2024 Jul 20;27(8):110552. doi: 10.1016/j.isci.2024.110552. eCollection 2024 Aug 16. iScience. 2024. PMID: 39171292 Free PMC article. - Hyperalgesic Effect Evoked by il-16 and its Participation in Inflammatory Hypernociception in Mice.
González-Rodríguez S, Sordo-Bahamonde C, Álvarez-Artime A, Baamonde A, Menéndez L. González-Rodríguez S, et al. J Neuroimmune Pharmacol. 2024 Aug 17;19(1):44. doi: 10.1007/s11481-024-10145-7. J Neuroimmune Pharmacol. 2024. PMID: 39152360 Free PMC article. - Cyclooxygenase-2 (COX-2)-dependent mechanisms mediate sleep responses to microbial and thermal stimuli.
Szentirmai É, Buckley K, Kapás L. Szentirmai É, et al. Brain Behav Immun. 2024 Nov;122:325-338. doi: 10.1016/j.bbi.2024.08.014. Epub 2024 Aug 10. Brain Behav Immun. 2024. PMID: 39134184 - Preoperative versus postoperative nonsteroidal anti-inflammatory drugs in femoroacetabular impingement patients undergoing hip arthroscopy surgery: analgesic effect, joint function, patients' satisfaction, and quality of life.
Guo Z, Liu G, Li W, Lu S, Zhao Y, Wang L, Cheng C. Guo Z, et al. Inflammopharmacology. 2024 Aug 10. doi: 10.1007/s10787-024-01540-w. Online ahead of print. Inflammopharmacology. 2024. PMID: 39126566 - Epigenetic Regulation and Molecular Mechanisms of Burn Injury-Induced Nociception in the Spinal Cord of Mice.
Mészár Z, Erdei V, Szücs P, Varga A. Mészár Z, et al. Int J Mol Sci. 2024 Aug 4;25(15):8510. doi: 10.3390/ijms25158510. Int J Mol Sci. 2024. PMID: 39126078 Free PMC article.
References
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Medical