The Role of Prostaglandin E1 as a Pain Mediator through Facilitation of Hyperpolarization-Activated Cyclic Nucleotide-Gated Channel 2 via the EP2 Receptor in Trigeminal Ganglion Neurons of Mice

• Published in: International journal of molecular sciences Vol. 22; no. 24; p. 13534
• Main Authors: Kwon, Jean, Choi, Young In, Jo, Hang Joon, Lee, Sang Hoon, Lee, Han Kyu, Kim, Heesoo, Moon, Jee Youn, Jung, Sung Jun
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 16.12.2021; MDPI
• Subjects: Action Potentials - physiology; Adenylate cyclase; Alprostadil - metabolism; Animals; Arachidonic acid; EP2; Erectile dysfunction; g-linolenic acid; Ganglia, Spinal - metabolism; HCN2 channel; Hyperalgesia; Hyperalgesia - metabolism; Hyperpolarization; Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels - metabolism; Immunohistochemistry; Inflammation; Ion channels (cyclic nucleotide-gated); Linolenic acid; Male; Mice; Mice, Inbred C57BL; Neuralgia - metabolism; Neurogenesis; Neurons; Nociceptors - metabolism; Nucleotides; Pain; Pain - metabolism; Pain Measurement - methods; Pain perception; PGE1; Potassium Channels - metabolism; Prostaglandin E1; Prostaglandin E2; Prostaglandin endoperoxide synthase; Receptors, Prostaglandin E, EP2 Subtype - metabolism; Smooth muscle; Therapeutic targets; Trigeminal ganglion; Trigeminal Ganglion - metabolism; trigeminal ganglion neuron; HCN2 channel; pain; trigeminal ganglion neuron; EP2; PGE1
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms222413534

Cyclooxygenase metabolizes dihomo-γ-linolenic acid and arachidonic acid to form prostaglandin (PG) E, including PGE1 and PGE2, respectively. Although PGE2 is well known to play an important role in the development and maintenance of hyperalgesia and allodynia, the role of PGE1 in pain is unknown. We confirm whether PGE1 induced pain using orofacial pain behavioral test in mice and determine the target molecule of PGE1 in TG neurons with whole-cell patch-clamp and immunohistochemistry. Intradermal injection of PGE1 to the whisker pads of mice induced a reduced threshold, enhancing the excitability of HCN channel-expressing trigeminal ganglion (TG) neurons. The HCN channel-generated inward current (I ) was increased by 135.3 ± 4.8% at 100 nM of PGE1 in small- or medium-sized TG, and the action of PGE1 on I showed a concentration-dependent effect, with a median effective dose (ED ) of 29.3 nM. Adenylyl cyclase inhibitor (MDL12330A), 8-bromo-cAMP, and the EP2 receptor antagonist AH6809 inhibited PGE1-induced I . Additionally, PGE1-induced mechanical allodynia was blocked by CsCl and AH6809. PGE1 plays a role in mechanical allodynia through HCN2 channel facilitation via the EP2 receptor in nociceptive neurons, suggesting a potential therapeutic target in that PGE1 could be involved in pain as endogenous substances under inflammatory conditions.