TRPV1 Receptors Contribute to Paclitaxel-Induced c-Fos Expression in Spinal Cord Dorsal Horn Neurons

Kalynovska, Nataliia; Adámek, Pavel; Paleček, J.

doi:10.33549/physiolres.933613

Cited by 21 publications

(20 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Sensory neurons within the spinal cord, once activated, express the immediate early gene c-fos (Hunt et al 1987). c-fos is a marker of neuronal activation in chronic pain states (Kalynovska et al 2017;Khasabov et al 2017) and is an indicator of spinal neuronal activation in diabetic neuropathic pain (Morgado et al 2010). There was an increase in c-fos expression in neurons (NeuN co-labelled) within the lumbar dorsal horn in the spinal cord in diabetic rats ( Fig.…”

Section: Resultsmentioning

confidence: 95%

See 1 more Smart Citation

Diabetes‐induced microvascular complications at the level of the spinal cord: a contributing factor in diabetic neuropathic pain

Ved

Lobo

Bestall

et al. 2018

The Journal of Physiology

View full text Add to dashboard Cite

Key points Diabetes is thought to induce neuropathic pain through activation of dorsal horn sensory neurons in the spinal cord.Here we explore the impact of hyperglycaemia on the blood supply supporting the spinal cord and chronic pain development.In streptozotocin‐induced diabetic rats, neuropathic pain is accompanied by a decline in microvascular integrity in the dorsal horn. Hyperglycaemia‐induced degeneration of the endothelium in the dorsal horn was associated with a loss in vascular endothelial growth factor (VEGF)‐A165b expression. VEGF‐A165b treatment prevented diabetic neuropathic pain and degeneration of the endothelium in the spinal cord.Using an endothelial‐specific VEGFR2 knockout transgenic mouse model, the loss of endothelial VEGFR2 signalling led to a decline in vascular integrity in the dorsal horn and the development of hyperalgesia in VEGFR2 knockout mice.This highlights that vascular degeneration in the spinal cord could be a previously unidentified factor in the development of diabetic neuropathic pain. AbstractAbnormalities of neurovascular interactions within the CNS of diabetic patients is associated with the onset of many neurological disease states. However, to date, the link between the neurovascular network within the spinal cord and regulation of nociception has not been investigated despite neuropathic pain being common in diabetes. We hypothesised that hyperglycaemia‐induced endothelial degeneration in the spinal cord, due to suppression of vascular endothelial growth factor (VEGF)‐A/VEGFR2 signalling, induces diabetic neuropathic pain. Nociceptive pain behaviour was investigated in a chemically induced model of type 1 diabetes (streptozotocin induced, insulin supplemented; either vehicle or VEGF‐A165b treated) and an inducible endothelial knockdown of VEGFR2 (tamoxifen induced). Diabetic animals developed mechanical allodynia and heat hyperalgesia. This was associated with a reduction in the number of blood vessels and reduction in Evans blue extravasation in the lumbar spinal cord of diabetic animals versus age‐matched controls. Endothelial markers occludin, CD31 and VE‐cadherin were downregulated in the spinal cord of the diabetic group versus controls, and there was a concurrent reduction of VEGF‐A165b expression. In diabetic animals, VEGF‐A165b treatment (biweekly i.p., 20 ng g−1) restored normal Evans blue extravasation and prevented vascular degeneration, diabetes‐induced central neuron activation and neuropathic pain. Inducible knockdown of VEGFR2 (tamoxifen treated Tie2CreERT2‐vegfr2flfl mice) led to a reduction in blood vessel network volume in the lumbar spinal cord and development of heat hyperalgesia. These findings indicate that hyperglycaemia leads to a reduction in the VEGF‐A/VEGFR2 signalling cascade, resulting in endothelial dysfunction in the spinal cord, which could be an undiscovered contributing factor to diabetic neuropathic pain.

show abstract

Section: Resultsmentioning

confidence: 95%

“…c‐fos is a marker of neuronal activation in chronic pain states (Kalynovska et al . ; Khasabov et al . ) and is an indicator of spinal neuronal activation in diabetic neuropathic pain (Morgado et al .…”

Section: Resultsmentioning

confidence: 99%

Diabetes‐induced microvascular complications at the level of the spinal cord: a contributing factor in diabetic neuropathic pain

Ved

Lobo

Bestall

et al. 2018

The Journal of Physiology

View full text Add to dashboard Cite

show abstract

“…Paclitaxel is known to induce neuropathic pain by increasing the expression of TRPV1 and TRPV4 pain receptors [ 29 – 31 ]. Therefore, the expression of the receptor under Paclitaxel treatment and under the combined treatment Pac-DSF was assayed by Realtime-PCR and Western blotting, the expression of the receptors under Paclitaxel treatment and evaluated the effect of DSF.…”

Section: Resultsmentioning

confidence: 99%

Probiotic DSF counteracts chemotherapy induced neuropathic pain

et al. 2018

View full text Add to dashboard Cite

Problem statement: Chemotherapy-induced peripheral neuropathy (CIPN) is a widespread and potentially disabling side effect of various anticancer drugs. In spite of the intensive research focused on obtaining therapies capable to treat or prevent CIPN, the medical demand remains very high. Microtubule-stabilizing agents, among which taxanes, are effective chemotherapeutic agents for the therapy of several oncologic diseases. The inflammatory process activated by chemotherapeutic agents has been interpreted as a potential trigger of the nociceptive process in CIPN. The chemotherapy-driven release of proinflammatory and chemokines has been recognized as one of the principal mechanisms controlling the establishment of CIPN. Several reports have indicated that probiotics are capable to regulate the balance of anti-inflammatory and pro-inflammatory cytokines. Accordingly, it has been suggested that some probiotic formulations, may have an effective role in the management of inflammatory pain symptoms. Experimental approaches used: we tested the hypothesis that paclitaxel-induced neuropathic pain can be counteracted by the probiotic DSF by using an in vitro model of sensitive neuron, the F11 cells. On this model, the biomolecular pathways involved in chemotherapy induced peripheral neuropathy depending on inflammatory cytokines were investigated by Real-time PCR, Western blotting and confocal microscopy. General conclusions: the results obtained, i.e. the increase of acetylated tubulin, the increase of the active forms of proteins involved in the establishment of neuropathic pain, point towards the use of this probiotic formulation as a possible adjuvant agent for counteracting CINP symptoms.

show abstract

“…An increased expression of TRPV1 in paclitaxel rat DRGs was also observed in later reports (Gao, Zan, Wang, Hu, & Huang, 2016). Accordingly, paclitaxel induces c‐fos expression—a marker of neuronal activation—in a TRPV1‐dependent manner (Kalynovska, Adamek, & Palecek, 2017). Also, TRPV1 protein overexpression was observed in rat peripheral tissues such as the paw skin (Hara et al, 2013).…”

Section: Taxane‐induced Peripheral Neuropathymentioning

confidence: 99%

Taxane‐induced neurotoxicity: Pathophysiology and therapeutic perspectives

Costa

Passos

Quintão

et al. 2020

British J Pharmacology

View full text Add to dashboard Cite

Taxane-derived drugs are antineoplastic agents used for the treatment of highly common malignancies. Paclitaxel and docetaxel are the most commonly used taxanes; however, other drugs and formulations have been used, such as cabazitaxel and nabpaclitaxel. Taxane treatment is associated with neurotoxicity, a well-known and relevant side effect, very prevalent amongst patients undergoing chemotherapy. Painful peripheral neuropathy is the most dose-limiting side effect of taxanes, affecting up to 97% of paclitaxel-treated patients. Central neurotoxicity is an emerging side effect of taxanes and it is characterized by cognitive impairment and encephalopathy. Besides impairing compliance to chemotherapy treatment, taxane-induced neurotoxicity (TIN) can adversely affect the patient's life quality on a long-term basis. Despite the clinical relevance, not many reviews have comprehensively addressed taxaneinduced neurotoxicity when they are used therapeutically. This article provides an up-to-date review on the pathophysiology of TIN and the novel potential therapies to prevent or treat this side effect. Abbreviations: Ca v , voltage-gated calcium; CB 1 , cannabinoid receptor 1; CB 2 , cannabinoid receptor 2; CCL2, chemokine (C-C motif) ligand 2; CCR2, CC motif chemokine receptor 2; CIPN, chemotherapy-induced peripheral neuropathy; CREB, cAMP response element-binding; CX3CL1, C-X3-C motif chemokine ligand 1; CXCL1, C-X3-C motif chemokine ligand 1; CXCL12, C-X-C motif chemokine ligand 12; CXCR1, C-X-C motif chemokine receptor 1; CXCR2, C-X-C motif chemokine receptor 2; DRG, dorsal root ganglion; GHS-R, growth hormone secretagogue receptor; IENFs, intra-epidermal nerve fibres; K ATP , ATP-sensitive potassium channel; K v , voltage-gated potassium channel; mPTP, mitochondrial permeability transition pore; Na v , voltage-gated sodium channel; Nrf2, nuclear factor-2 erythroid-related factor-2; PIPN, paclitaxel-induced peripheral neuropathy; TICN, taxane-induced central neurotoxicity; TIN, taxane-induced neurotoxicity; TIPN, taxane-induced peripheral neuropathy; TLR4, toll-like receptor-4; TRPA1, transient receptor potential cation channel subfamily A member 1; TRPV1, transient receptor potential cation channel subfamily V member 1; TRPV4, transient receptor potential cation channel subfamily V member 4.

show abstract

TRPV1 Receptors Contribute to Paclitaxel-Induced c-Fos Expression in Spinal Cord Dorsal Horn Neurons

Cited by 21 publications

References 18 publications

Diabetes‐induced microvascular complications at the level of the spinal cord: a contributing factor in diabetic neuropathic pain

Diabetes‐induced microvascular complications at the level of the spinal cord: a contributing factor in diabetic neuropathic pain

Probiotic DSF counteracts chemotherapy induced neuropathic pain

Taxane‐induced neurotoxicity: Pathophysiology and therapeutic perspectives

Contact Info

Product

Resources

About