Neurophysiological process - PGE2-induced pain processing

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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 [1].

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 [2], [3]. 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 (SLC21A2) [4].

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 PGE2R4 [3]. PGE2R2, PGE2R3 (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) [5].

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 transmission [1].

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 SCN10A.

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 [6]. Prostaglandin E2 has been shown to produce hyperalgesia by raising intracellular cAMP levels and PKA activation in nociceptive afferents [7], [8], [9]. Activated PKA can phosphorylate both Capsaicin receptor [10] and SCN10A [11]. 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) [6], [10], [12].

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) [13].

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 system [14].

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 [1].

References:

  1. Zeilhofer HU
    The glycinergic control of spinal pain processing. Cellular and molecular life sciences : CMLS 2005 Sep;62(18):2027-35
  2. Funk CD
    Prostaglandins and leukotrienes: advances in eicosanoid biology. Science (New York, N.Y.) 2001 Nov 30;294(5548):1871-5
  3. Hata AN, Breyer RM
    Pharmacology and signaling of prostaglandin receptors: multiple roles in inflammation and immune modulation. Pharmacology & therapeutics 2004 Aug;103(2):147-66
  4. Chan BS, Satriano JA, Schuster VL
    Mapping the substrate binding site of the prostaglandin transporter PGT by cysteine scanning mutagenesis. The Journal of biological chemistry 1999 Sep 3;274(36):25564-70
  5. Sugimoto Y, Narumiya S
    Prostaglandin E receptors. The Journal of biological chemistry 2007 Apr 20;282(16):11613-7
  6. Vanegas H, Schaible HG
    Prostaglandins and cyclooxygenases [correction of cycloxygenases] in the spinal cord. Progress in neurobiology 2001 Jul;64(4):327-63
  7. Taiwo YO, Levine JD
    Further confirmation of the role of adenyl cyclase and of cAMP-dependent protein kinase in primary afferent hyperalgesia. Neuroscience 1991;44(1):131-5
  8. Pitchford S, Levine JD
    Prostaglandins sensitize nociceptors in cell culture. Neuroscience letters 1991 Oct 28;132(1):105-8
  9. Taiwo YO, Bjerknes LK, Goetzl EJ, Levine JD
    Mediation of primary afferent peripheral hyperalgesia by the cAMP second messenger system. Neuroscience 1989;32(3):577-80
  10. Bhave G, Zhu W, Wang H, Brasier DJ, Oxford GS, Gereau RW 4th
    cAMP-dependent protein kinase regulates desensitization of the capsaicin receptor (VR1) by direct phosphorylation. Neuron 2002 Aug 15;35(4):721-31
  11. England S, Bevan S, Docherty RJ
    PGE2 modulates the tetrodotoxin-resistant sodium current in neonatal rat dorsal root ganglion neurones via the cyclic AMP-protein kinase A cascade. The Journal of physiology 1996 Sep 1;495 ( Pt 2):429-40
  12. Lopshire JC, Nicol GD
    The cAMP transduction cascade mediates the prostaglandin E2 enhancement of the capsaicin-elicited current in rat sensory neurons: whole-cell and single-channel studies. The Journal of neuroscience : the official journal of the Society for Neuroscience 1998 Aug 15;18(16):6081-92
  13. Harvey RJ, Depner UB, Wassle H, Ahmadi S, Heindl C, Reinold H, Smart TG, Harvey K, Schutz B, Abo-Salem OM, Zimmer A, Poisbeau P, Welzl H, Wolfer DP, Betz H, Zeilhofer HU, Muller U
    GlyR alpha3: an essential target for spinal PGE2-mediated inflammatory pain sensitization. Science (New York, N.Y.) 2004 May 7;304(5672):884-7
  14. Betz H, Laube B
    Glycine receptors: recent insights into their structural organization and functional diversity. Journal of neurochemistry 2006 Jun;97(6):1600-10

  1. Zeilhofer HU
    The glycinergic control of spinal pain processing. Cellular and molecular life sciences : CMLS 2005 Sep;62(18):2027-35
  2. Funk CD
    Prostaglandins and leukotrienes: advances in eicosanoid biology. Science (New York, N.Y.) 2001 Nov 30;294(5548):1871-5
  3. Hata AN, Breyer RM
    Pharmacology and signaling of prostaglandin receptors: multiple roles in inflammation and immune modulation. Pharmacology & therapeutics 2004 Aug;103(2):147-66
  4. Chan BS, Satriano JA, Schuster VL
    Mapping the substrate binding site of the prostaglandin transporter PGT by cysteine scanning mutagenesis. The Journal of biological chemistry 1999 Sep 3;274(36):25564-70
  5. Sugimoto Y, Narumiya S
    Prostaglandin E receptors. The Journal of biological chemistry 2007 Apr 20;282(16):11613-7
  6. Vanegas H, Schaible HG
    Prostaglandins and cyclooxygenases [correction of cycloxygenases] in the spinal cord. Progress in neurobiology 2001 Jul;64(4):327-63
  7. Taiwo YO, Levine JD
    Further confirmation of the role of adenyl cyclase and of cAMP-dependent protein kinase in primary afferent hyperalgesia. Neuroscience 1991;44(1):131-5
  8. Pitchford S, Levine JD
    Prostaglandins sensitize nociceptors in cell culture. Neuroscience letters 1991 Oct 28;132(1):105-8
  9. Taiwo YO, Bjerknes LK, Goetzl EJ, Levine JD
    Mediation of primary afferent peripheral hyperalgesia by the cAMP second messenger system. Neuroscience 1989;32(3):577-80
  10. Bhave G, Zhu W, Wang H, Brasier DJ, Oxford GS, Gereau RW 4th
    cAMP-dependent protein kinase regulates desensitization of the capsaicin receptor (VR1) by direct phosphorylation. Neuron 2002 Aug 15;35(4):721-31
  11. England S, Bevan S, Docherty RJ
    PGE2 modulates the tetrodotoxin-resistant sodium current in neonatal rat dorsal root ganglion neurones via the cyclic AMP-protein kinase A cascade. The Journal of physiology 1996 Sep 1;495 ( Pt 2):429-40
  12. Lopshire JC, Nicol GD
    The cAMP transduction cascade mediates the prostaglandin E2 enhancement of the capsaicin-elicited current in rat sensory neurons: whole-cell and single-channel studies. The Journal of neuroscience : the official journal of the Society for Neuroscience 1998 Aug 15;18(16):6081-92
  13. Harvey RJ, Depner UB, Wassle H, Ahmadi S, Heindl C, Reinold H, Smart TG, Harvey K, Schutz B, Abo-Salem OM, Zimmer A, Poisbeau P, Welzl H, Wolfer DP, Betz H, Zeilhofer HU, Muller U
    GlyR alpha3: an essential target for spinal PGE2-mediated inflammatory pain sensitization. Science (New York, N.Y.) 2004 May 7;304(5672):884-7
  14. Betz H, Laube B
    Glycine receptors: recent insights into their structural organization and functional diversity. Journal of neurochemistry 2006 Jun;97(6):1600-10

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