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.

Jean Kwon,Sang Hoon Lee,Heesoo Kim,Jee Youn Moon,Han Kyu Lee,Hang Joon Jo,Sung Jun Jung,Young In Choi

doi:10.3390/ijms222413534

Abstract

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 (Ih) was increased by 135.3 ± 4.8% at 100 nM of PGE1 in small- or medium-sized TG, and the action of PGE1 on Ih showed a concentration-dependent effect, with a median effective dose (ED50) of 29.3 nM. Adenylyl cyclase inhibitor (MDL12330A), 8-bromo-cAMP, and the EP2 receptor antagonist AH6809 inhibited PGE1-induced Ih. 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.

Highlights

Prostaglandin (PG) E is a family of naturally occurring prostaglandins, which are bioactive lipid autocoids
We examined whether Prostaglandin E1 (PGE1) affects orofacial pain behavior in mice
We demonstrated that PGE1 induced orofacial pain in a dose-dependent manner by facilitation of Ih in small- or medium-sized trigeminal ganglion (TG) neurons

Summary

Introduction

Prostaglandin (PG) E is a family of naturally occurring prostaglandins, which are bioactive lipid autocoids (prostanoids). PGE1 and PGE2, the two types of PGE, are metabolized from two different substrates of the lipid-peroxidizing enzyme cyclooxygenase (COX). The clinical usage of PGE1 focuses on its powerful vasodilatory and anti-inflammatory effects [3,4]. For its anti-inflammatory effects, PGE1 is used in rat arthritis [6] and lupus models [7]. The related mechanism of action of PGE1 is vasodilation through the accumulation of adenosine 30 ,50 cyclic monophosphate (cAMP) by G protein activation in vascular smooth muscle [3,8] and suppression of tumor necrosis factor-induced inflammation due to inhibition of nuclear factor-κB activation and reactive oxygen species production [9]

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Results

Conclusion