PGE2-induced pain processing
Prostaglandin E2 (PGE2) is a
crucial mediator of inflammatory pain sensitization. Prostaglandin
E2 is produced in response to inflammation both in peripheral inflamed
tissues and in the spinal cord .
Activation of the cytosolic phospholipase A2 (cPLA-2)
leads to release of arachidonic acid from cell membranes.
Consequently, arachidonic acid transformed into the
prostaglandin precursors Prostaglandin
G2 and Prostaglandin H2 by
constitutively expressed Cyclooxygenase-1 (COX-1) or
inducible Cyclooxygenase-2 (COX-2).
Prostaglandin H2 is further converted by Prostaglandin E
synthase (PGES) or Prostaglandin E synthase 2
(PGES2) into Prostaglandin E2
, . To act as signaling
molecules, prostaglandins must be released from the cells where they are synthesized.
Prostaglandin E2 can diffuse passively from the cell and/or
can be actively transported by Solute carrier organic anion transporter family member 2A1
Prostaglandin E2 exerts its function by acting on a group
of G-protein-coupled receptors. There are four subtypes of Prostaglandin E2 receptors
(also designated as subtype EP1, EP2, EP3 and EP4), PGE2R1,
PGE2R2, PGE2R3 and
(gamma isoform) and PGE2R4
couple to G-protein alpha-s resulting in stimulation of
Adenylate cyclase, increase Cyclic 3,5-adenosine
monophosphate (cAMP) levels and subsequent activation of
cAMP-dependent protein kinase A (PKA) .
Prostaglandin E2 signaling underlies alterations in
synaptic transmission within the spinal cord dorsal horn that plays a key role in the
development of inflammatory pain. Peripheral nociceptors make synaptic contacts with
local excitatory and inhibitory interneurons and central projection neurons, which convey
nociceptive information to higher central nervous system areas. The spinal cord dorsal
horn is the first site of synaptic integration in the pain pathway.
Prostaglandin E2 signaling can modulate both excitatory and
inhibitory neurotransmission (i) by increasing the responsiveness of peripheral
nociceptors that generate excitatory glutamatergic transmission, and (ii) by
disinhibition of dorsal horn neurons that are relived from inhibitory glycinergic
Prostaglandin E2 signaling is proposed to increase the
responsiveness of peripheral nociceptors in inflamed tissues probably via activation of
two types of ion channels, non-specific cation channel Capsaicin
receptor and tetrodoxin-resistant sodium channel
Capsaicin receptors are nonselective cation channels that
integrate multiple nociceptive stimuli. SCN10A channels are
selective sodium channels that are specifically expressed in nociceptive afferent nerve
fibers. Primary afferent neurons contain PGE2R3 and
PGE2R4 . Prostaglandin
E2 has been shown to produce hyperalgesia by raising intracellular
cAMP levels and PKA activation
in nociceptive afferents , , . Activated
PKA can phosphorylate both Capsaicin
receptor  and SCN10A . When activated, these channels open and produce membrane depolarization through
the influx of Na(+), but Capsaicin
receptor high Ca(2+) permeability is also
important for mediating the response to pain. Both actions increase the exitability of
peripheral nociceptors and facilitate the propagation of nociceptive signals along the
peripheral nerve. Glutamate (Glutamic acid) released from
these afferent neurons evokes glutamatergic neurotransmission, in particular via
N-methyl-D-aspartate receptor (NMDA
receptor) , , .
The other mechanism of PGE2-mediated spinal pain processing is disinhibition of dorsal
horn neurons. Prostaglandin E2 has been shown to inhibit
glycinergic inhibitory neurotransmission in the superficial layers of the dorsal horn in
the spinal cord. Peripheral inflammation induces the expression of
COX-2 and PGES2 in the spinal
cord. Prostaglandin E2 produced by these two enzymes
activates prostaglandin receptors of the EP2 subtype,
PGE2R2, the dorsal horn
neurons. PGE2R2 couples with a stimulatory
G-protein alpha-s protein and increases intracellular
cAMP. Subsequently, activated
PKA-cat phosphorylates and inhibits Glycine receptor alpha 3
subunit (GLRA3) .
The neuronal Glycine receptor is a ligand-gated chloride
channel involved in the inhibitory neurotransmission. When chloride channels open,
Cl(-) ions start entering the cell causing membrane
hyperpolarization and thus lower chance of a neurone attaining its excitatory threshold
for firing an action potential. Glycine receptors mediate
postsynaptic inhibition in the spinal cord and other regions of the central nervous
Glycine receptors are pentameric ion channels composed of
alpha and beta subunits (Glycine receptor alpha chain and
Glycine receptor beta chain).
GLRA3 in the spinal cord is distinctly expressed in the
superficial layers at the exact location where nociceptive afferent neurons make synaptic
connections with projection neurons. PGE2-induced phosphorylation of GLRA3
followed by inhibition of glycinergic neurotransmission leads to the
disinhibition of dorsal horn neurons, which then are able to transmit the nociceptive
signals to higher areas of the brain responsible of generating the conscious perception
of pain .
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