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mechanisms of neuropathic pain (spinal mechanisms (modulating elements ( …
mechanisms of neuropathic pain
peripheral mechanisms
peripheral sensitization
sensory denervation and sprouting of collateral nerve fibers
phenotypic switch
expression of ion channels
:<3: Na channels (Nav1.3, Nav1.7, Nav1.8) / dorsal root ganglia, terminal injury site
Ca channels ( :<3: N-type(CaV2.2 / dorsal root ganglia (*gabapentinoids, first-line treatment)), T-type(CaV3.2), L-type(CaV1.2))
K channels (hyper polarization activated cyclic nucleotide gate channel)
releasing inflammatory mediators ( :no_entry: CGRP, :no_entry: SP) / nociceptive terminals
-> releasing PG, bradykinin, GF, cytokines ( :no_entry: IL-1𝛽, :no_entry: TNF-𝛼)
sympathetically maintained pain
expression of 𝛼 adrenoceptors / primary afferent sensory fiber
sympathetic sprouting into dorsal root ganglia
spinal mechanisms
glia activation and pro inflammatory cytokines
pro inflammatory cytokines ( :no_entry: IL-1𝛽, IL-6, :no_entry: TNF-𝛼)
-> increasing PKC, 3',5'-cAMP
-> up regulation of glucocorticoid and glutamate r
glia activation
microglia
-> proliferating / dorsal root ganglia, spinal cord
-> releasing cytokines, chemokines, cytotoxic substances ( :no_entry: NO, free radicals)
:no_entry: Gal3-TLR4 pathway
:no_entry: expression of P2X4R
:fire: microglia apoptosis
:no_entry: mTOR pathway
astrocyte
-> releasing pronociceptive factor (PG, excitatory amino acids, cytokines)
:no_entry: Kindlin-1 / Wnt-10a signaling pathway
modulating elements
:<3: ion channels (Na, Ca, K)
inotropic and metabotropic receptors (glutamatergic r, GABAergic r, serotoninergic r, adrenergic r, neurokinin r, vanilloid r, :fire: melatonin r (MR1, MR2), :fire: opioid r (MOR, KOR) )
inflammatory cytokines (1L-2𝛽, IL-6, IL-8, TNF-𝛼) / glial cells
NGF
intracellular regulator (protein kinase (PKC), transcriptional factor (nuclear factor-𝜅B), 3',5'-cAMP)
:<3: spinal glutamatergic regulation -> increasing PKC
activating glutamate r
ionotropic glutamate r ( :no_entry: NMDA, AMPA)
metabotropic glutamate r (metabotropic glutamate r 2)
down regulation of glutamate transporter / spinal
:no_entry: BDNF
supraspinal mechanisms
variations in metabolism and concentrations of neurotransmitters / thalamus, cingulate cortex
cortical reorganization
changing in gene expression
altering corticotropin releasing factor signaling / limbic system
disinhibition
spinal cord level
loss of inhibitory current
dysfunctional GABA production and release / primary afferent terminal
increased Cl- level / inhibitory GABAergic interneuron
reduced activity of K+Cl- cotransporter
increased activity of Na+k+Cl- cotransporter
both
:no_entry: apoptosis of inhibitory GABAergic interneuron
:no_entry: decreased expression of KOR, MOR / dorsal root ganglia
secondary spinal neuron becoming less responsive to opioid
:fire: released opioids (dynorphin)
supraspinal level
diminution in tonic noradrenergic inhibition
a shift from a predominantly inhibitory role to a facilitative function for descending serotonergic modulation
:fire: up regulating brain opioid receptors