Oxaliplatin Depolarizes the IB4– Dorsal Root Ganglion Neurons to Drive the Development of Neuropathic Pain Through TRPM8 in Mice

Wu, Bin; Su, Xiaolin; Zhang, Wentong; Zhang, Yihong; Feng, Xinghua; Ji, Yonghua; Tan, Zhiyuan

doi:10.3389/fnmol.2021.690858

Cited by 18 publications

(18 citation statements)

References 62 publications

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“…Proprioception of experimental animals was also tested through the contact placing response and oxaliplatin treatment was shown to significantly hamper proprioception of treated animal. This may be due to damage in large DRG neurons, which is evident in the morphometrical analysis of the DGR neurons, in accordance with numerous other publications [ 18 , 21 , 73 , 74 ].…”

Section: Discussionsupporting

confidence: 90%

Antioxidant and Neuroprotective Effect of a Grape Pomace Extract on Oxaliplatin-Induced Peripheral Neuropathy in Rats: Biochemical, Behavioral and Histopathological Evaluation

et al. 2022

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Oxaliplatin is a widely used chemotherapeutic agent. Despite its many beneficial aspects in fighting many malignancies, it shares an aversive effect of neuropathy. Many substances have been used to limit this oxaliplatin-driven neuropathy in patients. This study evaluates the neuroprotective role of a grape pomace extract (GPE) into an oxaliplatin induced neuropathy in rats. For this reason, following the delivery of the substance into the animals prior to or simultaneously with oxaliplatin, their performance was evaluated by behavioral tests. Blood tests were also performed for the antioxidant activity of the extract, along with a histological and pathological evaluation of dorsal root ganglion (DRG) cells as the major components of the neuropathy. All behavioral tests were corrected following the use of the grape pomace. Oxidative stressors were also limited with the use of the extract. Additionally, the morphometrical analysis of the DRG cells and their immunohistochemical phenotype revealed the fidelity of the animal model and the changes into the parvalbumin and GFAP concentration indicative of the neuroprotective role of the pomace. In conclusion, the grape pomace extract with its antioxidant properties alleviates the harmful effects of the oxaliplatin induced chronic neuropathy in rats.

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Section: Discussionsupporting

confidence: 90%

Antioxidant and Neuroprotective Effect of a Grape Pomace Extract on Oxaliplatin-Induced Peripheral Neuropathy in Rats: Biochemical, Behavioral and Histopathological Evaluation

et al. 2022

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“…Multiple mechanisms are thought to be involved in CIPN. In particular, dysregulation of different ion channels, including sodium, potassium and TRP channels have been implicated in the painful symptoms 16–19 , 60 , 61 Our behavioural studies in TRPA1 KO mice defined a key role of this ion channel in the development of mechanical and cold hypersensitivity in oxaliplatin CIPN. Our findings are in line with previous pharmacological and genetic studies in mice and rats.…”

Section: Discussionmentioning

confidence: 91%

TRPA1 modulation by Sigma-1 receptor prevents oxaliplatin-induced painful peripheral neuropathy

Marcotti

Fernández-Trillo

González

et al. 2022

Brain

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Chemotherapy induced peripheral neuropathy (CIPN) is a frequent, disabling side effect of anticancer drugs. Oxaliplatin, a platinum compound used in the treatment of advanced colorectal cancer, often leads to a form of CIPN characterized by mechanical and cold hypersensitivity. Current therapies for CIPN are ineffective, often leading to the cessation of treatment. Transient receptor potential ankyrin 1 (TRPA1) is a polymodal, non-selective cation-permeable channel expressed in nociceptors, activated by physical stimuli and cellular stress products. TRPA1 has been linked to the establishment of CIPN and other painful neuropathic conditions. Sigma-1 receptor is an endoplasmic reticulum chaperone known to modulate the function of many ion channels and receptors. S1RA, a highly selective antagonist of Sigma-1 receptor has shown effectiveness in a phase II clinical trial for oxaliplatin CIPN. However, the mechanisms involved in the beneficial effects of S1RA are little understood. We combined biochemical and biophysical (i.e. intermolecular FRET) techniques to demonstrate the interaction between Sigma-1 receptor and human TRPA1. Pharmacological antagonism of Sigma-1R impaired the formation of this molecular complex and the trafficking of functional TRPA1 to the plasma membrane. Using patch-clamp electrophysiological recordings we found that antagonists of Sigma-1 receptor, including S1RA, exert a marked inhibition on plasma membrane expression and function of human TRPA1 channels. In TRPA1-expressing mouse sensory neurons, S1RA reduced inward currents and the firing of actions potentials in response to TRPA1 agonists. Finally, in a mouse experimental model of oxaliplatin neuropathy, systemic treatment with a S1RA prevented the development of painful symptoms by a mechanism involving TRPA1. In summary, the modulation of TRPA1 channels by Sigma-1 receptor antagonists suggests a new strategy for the prevention and treatment of CIPN and could inform the development of novel therapeutics for neuropathic pain.

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“…It is known that the painful peripheral neuropathy associated with the use of the chemotherapeutic drug oxaliplatin (OXA) is intensified by cold [ 49 ], and that TRPM8 channels play an important role in this debilitating condition [ 18 , 21 ]. In fact, the OXA-induced peripheral neuropathy mice model is being increasingly used to characterize TRPM8 antagonists.…”

Section: Resultsmentioning

confidence: 99%

“…Moreover, in both short- and long-term oxaliplatin-induced neuropathy animal models, both TRPA1 (HC033031) and TRPM8 (AMTB) antagonists attenuated the initially observed vasodilation after cold exposure [ 20 ]. Similarly, a recent study describes that oxaliplatin causes excitability of IB4 neurons, which can be attenuated by antagonists of TRPA1 (A-967079) and TRPM8 (TC-I), but not by capsazepine, a TRPV1 blocker, suggesting the contribution of cold channels in neuronal sensitization [ 21 ]. However, only the pretreatment with TC-I prevented cold and mechanical hypersensitivity induced by oxaliplatin, denoting key importance of the TRPM8 channel in the initial phase of sensitization.…”

Section: Introductionmentioning

confidence: 99%

β–Lactam TRPM8 Antagonist RGM8-51 Displays Antinociceptive Activity in Different Animal Models

Martín-Escura

Medina-Peris

Spear

et al. 2022

IJMS

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Transient receptor potential melastatin subtype 8 (TRPM8) is a cation channel extensively expressed in sensory neurons and implicated in different painful states. However, the effectiveness of TRPM8 modulators for pain relief is still a matter of discussion, since structurally diverse modulators lead to different results, depending on the animal pain model. In this work, we described the antinociceptive activity of a β–lactam derivative, RGM8-51, showing good TRPM8 antagonist activity, and selectivity against related thermoTRP channels and other pain-mediating receptors. In primary cultures of rat dorsal root ganglion (DRG) neurons, RGM8-51 potently reduced menthol-evoked neuronal firing without affecting the major ion conductances responsible for action potential generation. This compound has in vivo antinociceptive activity in response to cold, in a mouse model of oxaliplatin-induced peripheral neuropathy. In addition, it reduces cold, mechanical and heat hypersensitivity in a rat model of neuropathic pain arising after chronic constriction of the sciatic nerve. Furthermore, RGM8-51 exhibits mechanical hypersensitivity-relieving activity, in a mouse model of NTG-induced hyperesthesia. Taken together, these preclinical results substantiate that this TRPM8 antagonist is a promising pharmacological tool to study TRPM8-related diseases.

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Oxaliplatin Depolarizes the IB4– Dorsal Root Ganglion Neurons to Drive the Development of Neuropathic Pain Through TRPM8 in Mice

Cited by 18 publications

References 62 publications

Antioxidant and Neuroprotective Effect of a Grape Pomace Extract on Oxaliplatin-Induced Peripheral Neuropathy in Rats: Biochemical, Behavioral and Histopathological Evaluation

Antioxidant and Neuroprotective Effect of a Grape Pomace Extract on Oxaliplatin-Induced Peripheral Neuropathy in Rats: Biochemical, Behavioral and Histopathological Evaluation

TRPA1 modulation by Sigma-1 receptor prevents oxaliplatin-induced painful peripheral neuropathy

β–Lactam TRPM8 Antagonist RGM8-51 Displays Antinociceptive Activity in Different Animal Models

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