Table 5 A summary of the possible mechanisms involved in the development of oxaliplatin-induced neuropathic pain

Na⁺ channel

Prolonged open state and slow inactivation of the Na⁺ channels in acute OIPN

[12, 55,56,57]

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

[60, 61]

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

[64, 65]

Reduction in P/Q-, T-, and L-type Ca_v 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

[68, 69]

Oxaliplatin and oxalate cause TRPA1 sensitization to ROS

[70, 71]

Transporters

CTRs (CTR1) and OCTs (OCT2) mediate the uptake of OHP

[48, 72]

ATP7A and ATP7B facilitate the cellular efflux of OHP

[73]

Nuclear DNA damage

Formation of platinum DNA adducts

[57, 74].

Oxidative stress-related mitochondrial damage

Neuronal mitochondrial dysfunction resulting in nitro-oxidative stress

[2, 75]

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

[77, 78]

Lead to electron transport chain disruption and cellular energy failure in DRG neurons

[79]

Nrf2 may play a critical role in ameliorating OIPN

[67, 80]

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

[85,86,87,88,89]

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

[91,92,93]

GLT-1 and GLAST and EAAT1 dysfunction

[94, 95]

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

[101, 102]

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

[103, 104]

Microbiome-gut–brain and the neuroimmune–endocrine axis involved in the manifestations of OIPN

[103]