TABLE 4.
Papers that test interventions to the spinal cord that cause or treat CIPN symptoms.
| Author | Sample size and study design | Chemotherapy regimen | Effect of chemotherapy on CIPN symptoms and brain | Effects of CIPN intervention on the brain | Conclusion |
|---|---|---|---|---|---|
| Bráz et al. (2015) | C57BL/6 male mice VGAT mutant mice (deletion of vesicular GABA transporter) |
–Paclitaxel 1 mg/kg intraperitoneally 4 times every other day –Transplantation 1 week after hypersensitivity development |
–Paclitaxel caused mechanical and heat hypersensitivity –Paclitaxel decreased spinal cord expression of glutamic acid decarboxylase (GAD65 and 67; enzymes catalyzing the conversion of glutamate to GABA) –number of ATF3-positive (marker of sensory neuron damage) DRG neurons did not differ in the spinal cord of the paclitaxel and vehicle mice, and was lower than the peripheral nerve injury models –Levels of Iba-1 (marker of activated microglia) expression did not differ in the spinal cord of the paclitaxel and control mice, and the peripheral nerve injury produced a much greater activation of microglia |
–Intervention: Transplantation of MGE cells to restore GABAergic signaling in the spinal cord of wild-type and mutant mice –MGE transplantation in wild type mice reduced both mechanical and heat hypersensitivity; especially notable in heat –The transplant normalized GAD mRNA levels –MGE transplantation in VGAT mutant mice (lacking GABA transporter) did not reverse the mechanical or heat hypersensitivity |
–Paclitaxel produced mechanical and heat hypersensitivity and decreased spinal expression of GABA-producing enzymes –Injection of MGE cells that release GABA in the spinal cord mediated the reversal of the mechanical and heat hypersensitivities –MGE of mice with deletion of the vesicular GABA transporter (VGAT mutant) gene did not reverse hyperalgesia, suggesting that GABA itself caused the reduction in CIPN symptoms |
| Luo et al. (2019) | C57BL/6J mice | –Single paclitaxel 6 mg/kg intraperitoneal injection or multiple 2 mg/kg intraperitoneal injections on days 0, 2, 4, and 6 | –Paclitaxel caused mechanical allodynia, increased IL-17 in the CSF and spinal cord dorsal horn –IL-17R mRNA expressed on SOM+ neurons in the spinal dorsal horn –More positive resting membrane potential and a lower rheobase were observed in somatostatin-expressing neurons (SOM+; excitatory interneurons) neurons –Greater number of action potential firings in small-sized DRG neurons |
–Interventions
–IL-17 intrathecally –IL-17R-shRNA injected in the intra-dorsal horn of SOM-Cre mice –GABA and Glycine bath application –IL-17 caused a transient reduction of paw withdrawal threshold and increased the amplitude of NMDAR-EPSC evoked by dorsal root entry zone –SOM+ perfusion with IL-17 induced a rapid increase in the frequency but not amplitude of sEPSCs –IL-17 inhibited GABA-induced currents but had no effect on glycine-induced currents in spinal SOM+ neurons –Blocking IL-17R with a neutralizing antibody resulted in opposite changes in excitatory and inhibitory synaptic transmission in lamina IIo SOM+ neurons of paclitaxel-treated animals –In DRG neurons, IL-17RA antibody treatment suppressed excitability increase –Knockdown of IL-17R in spinal SOM+ neurons delayed and suppressed paclitaxel-induced mechanical allodynia –Selective knockdown of IL-17R in spinal SOM+ neurons suppressed the frequency, but not the amplitude of sEPSCs |
–Paclitaxel increased levels of pro-inflammatory cytokine IL-17, created a more positive resting potential in excitatory interneurons and increased neural activity –IL-17 enhanced excitatory synaptic transmission, potentiated NMDA-mediated eEPSCs in spinal cord slices, decreased the inhibitory control of SOM+ neurons and suppressed GABA-induced currents –IL-17 decreased inhibitory postsynaptic potentials and GABA-induced currents –Knockdown or blockage of IL-17 attenuated neural excitability and reversed CIPN symptoms |
| Mannelli et al. (2015) | Male Sprague Dawley rats –8 Rats/treatment in 2 different experimental sets |
–Oxaliplatin 2.4 mg/kg intraperitoneally 5 days/week for 2 weeks –Cerebral cortex synaptosomes (purified nerve terminals) prepared on day 15 of oxaliplatin treatment |
–Oxaliplatin induced mechanical hypersensitivity –Increased P2X7-evoked glutamate release from cerebrocortical synaptosomes –Higher ATP overflow in oxaliplatin-treated synaptosomes |
–Intervention: BBG and A-438079 (P2X7 receptor antagonists) and Erioglaucine and10Panx (Pannexin 1 selective inhibitors) intrathecal in-vivo injections –P2X7-evoked glutamate release was eliminated by BBG and A-438079 –P2X7-evoked glutamate release was reduced by Carbenoxolone and Erioglaucine and10Panx –BBG, Erioglaucine and10Panx reversed oxaliplatin-induced pain |
–Oxaliplatin induced mechanical hypersensitivity –Oxaliplatin increased P2X7R-depedant glutamate release in cerebrocortical nerve terminals, through Pannexin 1 recruitment –P2X7R antagonists and Pannexin 1 inhibitors eliminated or reduced the glutamate release, respectively, and eliminated oxaliplatin-induced pain |
| Morioka et al. (2019) | Male ddy mice | –Paclitaxel 2 mg/kg intraperitoneally once/day for 5 times every other day | –Paclitaxel caused mechanical hypersensitivity | –Intervention: intrathecal treatment of 100 or 300 nmol of SR9009 (agonist of REV-ERB, nuclear receptors related to regulation of metabolism, inflammation, and tumor growth) –SR9009 reduced the paclitaxel-induced mechanical hypersensitivity |
–Paclitaxel induced mechanical hypersensitivity, which was significantly reduced by stimulating REV-ERB transcription factors |
| Maruta et al. (2019) | Male Sprague Dawley rats 5 rats |
–Oxaliplatin 4 mg/kg intraperitoneally twice/week for 4 weeks –Electronic von Frey performed 1 week before and 1 week after oxaliplatin treatment |
–Oxaliplatin caused mechanical allodynia –Increased ERK1/2 phosphorylation in the DRG up to 4.5-fold –Increased brain-derived neurotrophic factor (BDNF) in the DRG |
–Intervention: PD98059 (ERK inhibitor) intrathecally –PD98059 inhibited mechanical allodynia –PD98059 inhibited upregulation of ERK phosphorylation in the DRG |
–Oxaliplatin administration induced chronic mechanical allodynia and increased ERK1/2 phosphorylation in the DRG –ERK inhibitor prevented mechanical allodynia by inhibiting oxaliplatin-induced upregulation of ERK phosphorylation |
| Nie et al. (2018) | Male Sprague Dawley rats AKAP150flox/flox mice (inhibition of AKAP150) –Control vehicle 12 rats in each group |
–Paclitaxel 8 mg/kg intraperitoneally on 3 alternate days (days 1, 4 and 7, cumulative dose 24 mg/kg) in rats –Paclitaxel 2 mg/kg intraperitoneally for 5 consecutive days in mice |
–Paclitaxel induced mechanical allodynia and thermal hyperalgesia –Paclitaxel increased mRNA and protein expression of A-kinase anchor protein 150 (AKAP150; accessory protein targeting enzymes involved in pain-related pathogenesis) in the DRG –Paclitaxel decreased enzyme activity of calcineurin (CN, a calcium and calmodulin dependent serine/threonine protein phosphatase that activates T cells) –Paclitaxel decreased nucleus NFAT2 (protein involved in T cell activation and differentiation) levels –Paclitaxel increased AKAP150 interaction with CN, decreased IL-10 mRNA (anti-inflammatory cytokine), decreased IL-13 mRNA (anti-inflammatory), which returned to normal level on day 10, decreased IL-4 mRNA (anti-inflammatory cytokine), and decreased NFAT2 binding to the IL-4 promoter in the DRG |
–Interventions –AKAP150 siRNA (AKAP150 knockdown) –AKAP150flox/flox mice (AKAP150 inhibition) –Intrathecal FK506 (CN enzyme activity inhibitor) -AAV5-Cre-GFP (AKAP150 knockdown) –AAV5- NFAT2-GFP (overexpress NFAT2) –IL-4 siRNA (IL-4 knockdown) –Intrathecal CN –CN increased NFAT2 levels –AKAP150 siRNA attenuated the mechanical allodynia and thermal hyperalgesia –CN enzyme activity increased in AKAP150flox/flox mice injected with AAV5-Cre-GFP –AKAP150 knock down restored IL-4 –FK506 decreased NFAT2 expression in DRG nuclei –Intrathecal injection of IL-4 normalized hyperactivity of DRG neurons and attenuated mechanical allodynia and thermal hyperalgesia –NFAT2 increased after AAV5-NFAT2-GFP injections, which attenuated mechanical allodynia and thermal hyperalgesia –FK506 induced mechanical allodynia and thermal hyperalgesia –AAV5-NFAT2-GFP partly restored the decreased IL-4 expression and restored NFAT2 binding to IL-4 promoter –Knockdown of IL-4 abolished the analgesic effect of over-expression in NFAT2 |
–Paclitaxel increased AKAP150, decreased NFAT2, IL-10, IL-13, IL-4 levels, decreased calcineurin activity, and decreased interaction of NFAT2 with IL-4 –AKAP150 increased in response to paclitaxel and its knockdown reduced CIPN symptoms, increased calcineurin activity, and restored IL-4 levels –IL-4 decreased the enhanced action potentials within the DRG and reduced CIPN symptoms, and its downregulation contributed to enhanced CIPN symptoms –Increased NFAT2 reduced CIPN symptoms, potentially through restoring IL-4 levels –Regulation of IL-4 via the calcineurin/NFAT2 pathway mediated by AKAP150 (the decreased CN activity) inhibited the nuclei import of NFAT2 and the decreased NFAT2 reduced the IL-4 expression and participated in paclitaxel- induced neuropathic pain. Thus, up-regulated AKAP150 after paclitaxel injection was involved in neuropathic pain through inhibiting the enzyme activity of calcineurin, which might modulate the translocation of NFAT2 in the above conditions |
| Thibault et al. (2014) | Male Sprague Dawley rats 123 total
–57 vincristine vs. 30 vehicle controls –6 Vincristine-oxycodone-saclofen treated –6 Vincristine-oxycodone-saline treated –6 Vincristine-saline-saclofen treated –6 Vincristine-saline-saline treated –6 Vincristine-morphine-saclofen treated –6 Vincristine-morphine-saline |
–vincristine 0.1 mg/kg/day intraperitoneally for 2 five-day cycles with a two-day pause between cycles –Behavioral tests were performed on days 1 and 15 of vincristine treatment –The study of oxycodone and morphine effects was performed on days 15 and 19 (chronic) |
–Vincristine-treated rats displayed increased static mechanical allodynia, hyperalgesia, and dynamic mechanical allodynia in comparison to baseline and saline-treated rats | –Interventions
–Oxycodone intraperitoneally –Morphine intraperitoneally –Saclofen (GABAB receptor antagonist) intrathecally –A single morphine or oxycodone injection reversed static mechanical allodynia, hyperalgesia and dynamic mechanical allodynia ◦ oxycodone was more effective than morphine to reduce static mechanical analgesia ◦ oxycodone reversed dynamic mechanical hyperesthesia but morphine only attenuated it –At the end of the analgesic chronic treatment on day 19, only oxycodone was able to maintain the analgesic effect on mechanical sensitivity –Following oxycodone treatment, 3 genes regulating receptor activity were observed in the small diameter DRG neurons, as well as their terminals in superficial laminae of the dorsal horn: Gabbr2 (GABAB2 receptor), Gabrb3 (GABAA R subunit β3) and Gabrg1 (GABAA R subunit γ1) –The analgesic effect of oxycodone on static mechanical allodynia was completely blocked by Saclofen, whereas its analgesic effect on mechanical hyperalgesia was only partially blocked |
–Vincristine increased static mechanical allodynia, hyperalgesia, and dynamic mechanical allodynia –Oxycodone had longer lasting analgesic effects than morphine on vincristine-treated animals –Oxycodone only caused an upregulation of various GABA receptor transcripts in the DRG –The relieving effects of oxycodone, but not morphine, were either partially or completely blocked by GABAB receptor antagonist |
| Yadav et al. (2015) | Male Sprague Dawley rats | –Paclitaxel 2 mg/kg intraperitoneally on 4 alternate days (days 1, 3, 5 and 7) | –Paclitaxel caused thermal hyperalgesia and mechanical allodynia –Paclitaxel decreased GABAergic inhibition in the dorsal horn in comparison to vehicle rats –Paclitaxel increased GAT-1 (presynaptic and astrocytic GABA transporter) and decreased GAT-3 (astrocytic GABA transporter) expression in the dorsal horn –Paclitaxel increased GABA uptake |
–Interventions –Intrathecal NO-711 (GAT-1 inhibitor) –Intrathecal SNAP5114 (GAT-3 inhibitor) –The paclitaxel-induced GABAergic suppression was alleviated by blocking GAT-1 but not GAT-3 –The thermal hyperalgesia and mechanical allodynia were significantly reversed by blocking GAT-1 but not GAT-3 |
–Paclitaxel induced thermal hyperalgesia and mechanical allodynia, decreased GABA signaling, and increased GABA uptake in the dorsal horn –Paclitaxel increased GAT-1 expression, and decreased GAT-3 expression in the dorsal horn –Blocking GAT-1 decreased the paclitaxel-induced GABA suppression and CIPN symptoms. These results were not observed with GAT-3 blockage |