Neurophysiological process PGE2-induced pain processing
PGE2-induced pain processing
Prostaglandin E2 (PGE2) is a crucial mediator of inflammatory painsensitization. Prostaglandin E2 is produced in response to inflammation both inperipheral inflamed tissues and in the spinal cord [1].
Activation of the cytosolic phospholipase A2 ( cPLA-2 ) leads to release ofarachidonic acid from cell membranes. Consequently, a rachidonic acidtransformed into the prostaglandin precursors Prostaglandin G2 andProstaglandin H2 by constitutively expressed Cyclooxygenase-1 ( COX-1 ) orinducible Cyclooxygenase-2 ( COX-2 ). Prostaglandin H2 is further convertedby Prostaglandin E synthase ( PGES ) or Prostaglandin E synthase 2 ( PGES2) into Prostaglandin E2 [2], [3]. To act as signalingmolecules, prostaglandins must be released from the cells where they are synthesized.Prostaglandin E2 can diffuse passively from the cell and/or can be activelytransported by Solute carrier organic anion transporter family member 2A1 (SLC21A2 ) [4].
Prostaglandin E2 exerts its function by acting on a group of G-protein-coupledreceptors. There are four subtypes of Prostaglandin E2 receptors (also designated assubtype EP1, EP2, EP3 and EP4), PGE2R1, PGE2R2, PGE2R3 andPGE2R4 [3]. PGE2R2, PGE2R3 (gamma isoform) andPGE2R4 couple to G-protein alpha-s resulting in stimulation of Adenylatecyclase, increase Cyclic 3,5-adenosine monophosphate ( cAMP ) levels andsubsequent activation of cAMP-dependent protein kinase A ( PKA ) [5].
Prostaglandin E2 signaling underlies alterations in synaptic transmissionwithin the spinal cord dorsal horn that plays a key role in the development ofinflammatory pain. Peripheral nociceptors make synaptic contacts with local excitatoryand inhibitory interneurons and central projection neurons, which convey nociceptiveinformation to higher central nervous system areas. The spinal cord dorsal horn is thefirst site of synaptic integration in the pain pathway. Prostaglandin E2 signalingcan modulate both excitatory and inhibitory neurotransmission (i) by increasing theresponsiveness of peripheral nociceptors that generate excitatory glutamatergictransmission, and (ii) by disinhibition of dorsal horn neurons that are relived frominhibitory glycinergic transmission [1].
Prostaglandin E2 signaling is proposed to increase the responsiveness ofperipheral nociceptors in inflamed tissues probably via activation of two types of ionchannels, non-specific cation channel Capsaicin receptor and tetrodoxin-resistantsodium channel SCN10A.
Capsaicin receptors are nonselective cation channels that integrate multiplenociceptive stimuli. SCN10A channels are selective sodium channels that arespecifically expressed in nociceptive afferent nerve fibers. Primary afferent neuronscontain PGE2R3 and PGE2R4 [6]. Prostaglandin E2 hasbeen shown to produce hyperalgesia by raising intracellular cAMP levels andPKA activation in nociceptive afferents [7], [8], [9]. Activated PKA can phosphorylate both Capsaicin receptor [10] and SCN10A [11]. When activated, these channels open andproduce membrane depolarization through the influx of Na(+), but Capsaicinreceptor high Ca(2+) permeability is also important for mediating the responseto pain. Both actions increase the exitability of peripheral nociceptors and facilitatethe propagation of nociceptive signals along the peripheral nerve. Glutamate (Glutamic acid ) released from these afferent neurons evokes glutamatergicneurotransmission, in particular via N-methyl-D-aspartate receptor ( NMDAreceptor ) [12], [6], [10].
The other mechanism of PGE2-mediated spinal pain processing is disinhibition of dorsalhorn neurons. Prostaglandin E2 has been shown to inhibit glycinergic inhibitoryneurotransmission in the superficial layers of the dorsal horn in the spinal cord.Peripheral inflammation induces the expression of COX-2 and PGES2 in thespinal cord. Prostaglandin E2 produced by these two enzymes activatesprostaglandin receptors of the EP2 subtype, PGE2R2, the dorsal horn neurons.PGE2R2 couples with a stimulatory G-protein alpha-s protein and increasesintracellular cAMP. Subsequently, activated PKA-cat phosphorylates andinhibits Glycine receptor alpha 3 subunit ( GLRA3 ) [13].
The neuronal Glycine receptor is a ligand-gated chloride channel involved inthe inhibitory neurotransmission. When chloride channels open, Cl(-) ions startentering the cell causing membrane hyperpolarization and thus lower chance of a neuroneattaining its excitatory threshold for firing an action potential. Glycinereceptors mediate postsynaptic inhibition in the spinal cord and other regions of thecentral nervous system [14].
Glycine receptors are pentameric ion channels composed of alpha and betasubunits ( Glycine receptor alpha chain and Glycine receptor beta chain). GLRA3 in the spinal cord is distinctly expressed in the superficial layers atthe exact location where nociceptive afferent neurons make synaptic connections withprojection neurons. PGE2-induced phosphorylation of GLRA3 followed by inhibitionof glycinergic neurotransmission leads to the disinhibition of dorsal horn neurons, whichthen are able to transmit the nociceptive signals to higher areas of the brainresponsible of generating the conscious perception of pain [1].
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