mechanisms of neuropathic pain
peripheral mechanisms
peripheral sensitization
sensory denervation and sprouting of collateral nerve fibers
phenotypic switch
expression of ion channels
sympathetically maintained pain
spinal mechanisms
glia activation and pro inflammatory cytokines
supraspinal mechanisms
disinhibition
spinal cord level
supraspinal level
releasing inflammatory mediators ( ⛔ CGRP, ⛔ SP) / nociceptive terminals
❤ Na channels (Nav1.3, Nav1.7, Nav1.8) / dorsal root ganglia, terminal injury site
Ca channels ( ❤ 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)
expression of 𝛼 adrenoceptors / primary afferent sensory fiber
sympathetic sprouting into dorsal root ganglia
modulating elements
❤ ion channels (Na, Ca, K)
inotropic and metabotropic receptors (glutamatergic r, GABAergic r, serotoninergic r, adrenergic r, neurokinin r, vanilloid r, 🔥 melatonin r (MR1, MR2), 🔥 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)
❤ spinal glutamatergic regulation -> increasing PKC
activating glutamate r
down regulation of glutamate transporter / spinal
ionotropic glutamate r ( ⛔ NMDA, AMPA)
metabotropic glutamate r (metabotropic glutamate r 2)
pro inflammatory cytokines ( ⛔ IL-1𝛽, IL-6, ⛔ TNF-𝛼)
glia activation
microglia
astrocyte
-> proliferating / dorsal root ganglia, spinal cord
-> releasing cytokines, chemokines, cytotoxic substances ( ⛔ NO, free radicals)
-> releasing pronociceptive factor (PG, excitatory amino acids, cytokines)
-> increasing PKC, 3',5'-cAMP
-> up regulation of glucocorticoid and glutamate r
-> releasing PG, bradykinin, GF, cytokines ( ⛔ IL-1𝛽, ⛔ TNF-𝛼)
variations in metabolism and concentrations of neurotransmitters / thalamus, cingulate cortex
cortical reorganization
changing in gene expression
altering corticotropin releasing factor signaling / limbic system
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
⛔ apoptosis of inhibitory GABAergic interneuron
⛔ decreased expression of KOR, MOR / dorsal root ganglia
secondary spinal neuron becoming less responsive to opioid
diminution in tonic noradrenergic inhibition
a shift from a predominantly inhibitory role to a facilitative function for descending serotonergic modulation
⛔ Gal3-TLR4 pathway
⛔ Kindlin-1 / Wnt-10a signaling pathway
⛔ expression of P2X4R
🔥 microglia apoptosis
⛔ mTOR pathway
🔥 up regulating brain opioid receptors
🔥 released opioids (dynorphin)
⛔ BDNF