Targets | Mechanisms | References |
---|---|---|
Na+ channel | Prolonged open state and slow inactivation of the Na+ channels in acute OIPN | |
Induced abnormalities of Na+ currents in chronic OIPN | [58] | |
K+ channel | Increasing the expression of the pro-excitatory K+ channels | [59] |
Decreased expression of two-pore domain K+ channels (TREK-1 and TRAAK) in DRG | ||
CAG repeat polymorphisms in the KCNN3 gene | [62] | |
Ca2+ channel | Oxalate as a calcium chelator contributes to the acute form of OIPN | [63] |
Increased expression of the Cavα2δ – 1 subunit mRNA and protein in cold hypersensitivity | ||
Reduction in P/Q-, T-, and L-type Cav channel currents | [66] | |
Transient receptor potential channels | Up-regulation of the mRNA of the TRPV1, TRPA1, and TRPM8 in cultured DRG neurons | [67] |
OHP-induced cold allodynia in vivo was found to enhance the sensitivity and expression of TRPM8 and TRPA1 | ||
Oxaliplatin and oxalate cause TRPA1 sensitization to ROS | ||
Transporters | CTRs (CTR1) and OCTs (OCT2) mediate the uptake of OHP | |
ATP7A and ATP7B facilitate the cellular efflux of OHP | [73] | |
Nuclear DNA damage | Formation of platinum DNA adducts | |
Oxidative stress-related mitochondrial damage | Neuronal mitochondrial dysfunction resulting in nitro-oxidative stress | |
Bind to mitochondrial DNA and formation of adducts | [76] | |
Oxidative stress could gate TRPA1, produce nociceptive responses and neurogenic inflammation, and cause demyelination and disruption of the cytoskeleton of peripheral nerves | ||
Lead to electron transport chain disruption and cellular energy failure in DRG neurons | [79] | |
Nrf2 may play a critical role in ameliorating OIPN | ||
Activation of the immune system and neuroinflammation | Increased levels of CCL2 and CCR2 accompanied by mechanical hypersensitivity | [81] |
IL-8 signaling pathway is involved in neuroinflammation | [82] | |
Gut microbiota -TLR4 activation on macrophages | [83] | |
Increased circulating CD4 + and CD8 + T-cells | [84] | |
Glia activation | Increase of neuro-immune activation resulting in converted neurotransmission | |
Transient activation of microglia and astrocytes in the spinal cord and supraspinal areas | ||
Schwann cells | Mitochondrial dysfunction in Schwann cells | [90] |
Central nervous system structures and neurotransmitters | Altered levels of neurotransmitters, such as catecholamines, histamine, serotonin, glutamate, and GABA | |
GLT-1 and GLAST and EAAT1 dysfunction | ||
Caspases and MAP-kinases, Protein kinase C, and PI3K/Akt2 pathway | Early activation of the MAP-kinase proteins p38 and ERK1/2, which promotes apoptosis-mediated cell death in rat DRG neurons | [96] |
Up-regulates the gamma isoforms of PKC and increases in the phosphorylation of gamma/epsilon PKC isoforms | [97] | |
PI3K/Akt2 activation | [98] | |
MicroRNA regulation | MiR-15b down-regulation of BACE1 contributes to chronic neuropathic pain | [99] |
Gut microbiota | Different microbe-associated molecular patterns (MAMPs) bind to their TLRs | [100] |
LPS can directly mediate the gating of TRPA1 and increase calcium influx | ||
Chemotherapy decreased numbers of “beneficial” bacteria, such as Lactobacillus and Bifidobacteria, while Lactobacillus acidophilus exerts anti-tumor effects while preventing the incidence of the toxic adverse events | ||
Microbiome-gut–brain and the neuroimmune–endocrine axis involved in the manifestations of OIPN | [103] |