May a sigma‐1 antagonist improve neuropathic signs induced by cisplatin and vincristine in rats?

Abstract

Background The antineoplastic drugs cisplatin and vincristine induce peripheral neuropathies. The sigma‐1 receptor (σ1R) is expressed in areas of pain control, and its blockade with the novel selective antagonist MR‐309 has shown efficacy in nociceptive and neuropathic pain models. Our goal was to test whether this compound reduces neuropathic signs provoked by these antitumoural drugs. Methods Rats were treated with cisplatin or vincristine to induce neuropathies. The effects of acute or repeated administration of MR‐309 were tested on mechanical and thermal sensitivity, electrophysiological activity of Aδ‐primary afferents in the rat skin–saphenous nerve preparation, and gastrointestinal or cardiovascular functions. Results Rats treated with antitumourals developed tactile allodynia, while those treated with vincristine also developed mechanical hyperalgesia. These in vivo modifications correlated with electrophysiological hyperactivity (increased spontaneous activity and hyperresponsiveness to innocuous and noxious mechanical stimulation). Animals treated with cisplatin showed gastrointestinal impairment and those receiving vincristine showed cardiovascular toxicity. A single dose of MR‐309 strongly reduced both nociceptive behaviour and electrophysiological changes. Moreover, its concomitant administration with the antitumourals blocked the development of neuropathic symptoms, thus restoring mechanical sensitivity, improving the impairment of feeding behaviour and gastrointestinal transit in the cisplatin‐treated group along with ameliorating the altered vascular reactivity recorded in rats treated with vincristine. Conclusion σ1R antagonist, MR‐309, reduces sensorial and electrophysiological neuropathic signs in rats treated with cisplatin or vincristine and, in addition, reduces gastrointestinal and cardiovascular side effects. Significance σ1R antagonism could be an interesting and new option to palliate antitumoural neuropathies.

Cardiovascular Toxicity Induced by Chronic Vincristine Treatment

“…The data obtained in the present work show that after chronic treatment with vincristine, there is significant damage to endothelial-dependent vasodilation in the aorta and severe contractile dysfunction in the mesenteric bed. These findings confirm the results previously obtained by our research group ( Paniagua et al, 2018 ), also demonstrating that these functional alterations at the vascular level appear earlier than others, such as cardiac alterations. Other authors have also shown the presence of endothelial toxicity after treatment with other antitumor drugs such as anthracyclines, cisplatin, taxanes, or 5-fluorouracil ( Di Lisi et al, 2017 ), with this toxicity appearing before cardiac toxicity in the case of cisplatin treatment ( Herradón et al, 2017 ).…”

“…In this sense, experimental studies offer a useful alternative for evaluating the toxicity of antitumor agents and their possible mechanisms of action. In this work, the experimental model developed has already been used by different authors for the evaluation of gastrointestinal, hepatic, and hematological toxicity and peripheral neuropathy caused by vincristine ( Bessaguet et al, 2018 ; Paniagua et al, 2018 ; Geisler, 2021 ), which validates it as useful for the deeper analysis of the cardiovascular toxicity caused by this antitumor agent. To date, few experimental studies have evaluated the cardiovascular toxicity of vincristine.…”

“…Previously, our research group has described that chronic vincristine treatment causes cardiovascular alterations in rats that mainly affect vascular function, provoking an increase in coronary perfusion pressure and hyperresponsiveness of contractile function and an endothelium-dependent vasorelaxant dysfunction in the aorta ( Paniagua et al, 2018 ). The present study aimed to analyze whether these alterations remain after the chemotherapy treatment suspension (sequelae) and evaluate the possible mechanisms involved in this vascular damage.…”

Sigma-1 Receptor in Retina: Neuroprotective Effects and Potential Mechanisms

“…The sigma-1 receptor antagonist showed analgesic effects to relieve the symptoms in several peripheral neuropathy models [ 153 , 154 , 155 , 156 ]. MR309, a selective and novel antagonist of the sigma-1 receptor [ 164 ], has been tested in a phase II clinical trial, suggesting the promising action for oxaliplatin-induced peripheral neuropathic pain relief in patients [ 165 ]]. A good deal of evidence supported that the sigma-1 receptor was a promising target for cancer treatment although there was no clinical drugs application.…”