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Tetrodotoxin, a Potential Drug for Neuropathic and Cancer Pain Relief?

ABSTRACT: Tetrodotoxin (TTX) is a potent neurotoxin found mainly in puffer fish and other marine and terrestrial animals. TTX blocks voltage-gated sodium channels (VGSCs) which are typically classified as TTX-sensitive or TTX-resistant channels. VGSCs play a key role in pain signaling and some TTX-sensitive VGSCs are highly expressed by adult primary sensory neurons. During pathological pain conditions, such as neuropathic pain, upregulation of some TTX-sensitive VGSCs, including the massive re-expression of the embryonic VGSC subtype NaV1.3 in adult primary sensory neurons, contribute to painful hypersensitization. In addition, people with loss-of-function mutations in the VGSC subtype NaV1.7 present congenital insensitive to pain. TTX displays a prominent analgesic effect in several models of neuropathic pain in rodents. According to this promising preclinical evidence, TTX is currently under clinical development for chemo-therapy-induced neuropathic pain and cancer-related pain. This review focuses primarily on the preclinical and clinical evidence that support a potential analgesic role for TTX in these pain states. In addition, we also analyze the main toxic effects that this neurotoxin produces when it is administered at therapeutic doses, and the therapeutic potential to alleviate neuropathic pain of other natural toxins that selectively block TTX-sensitive VGSCs.

SUBMITTER: Gonzalez-Cano R

PROVIDER: S-EPMC8310002 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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Tetrodotoxin, a Potential Drug for Neuropathic and Cancer Pain Relief?

González-Cano Rafael R Ruiz-Cantero M Carmen MC Santos-Caballero Miriam M Gómez-Navas Carlos C Tejada Miguel Á MÁ Nieto Francisco R FR

Toxins 20210712 7

Tetrodotoxin (TTX) is a potent neurotoxin found mainly in puffer fish and other marine and terrestrial animals. TTX blocks voltage-gated sodium channels (VGSCs) which are typically classified as TTX-sensitive or TTX-resistant channels. VGSCs play a key role in pain signaling and some TTX-sensitive VGSCs are highly expressed by adult primary sensory neurons. During pathological pain conditions, such as neuropathic pain, upregulation of some TTX-sensitive VGSCs, including the massive re-expression ...[more]

PMID: 34357955

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Project description:BackgroundNeuropathic pain is characterized by pain hypersensitivity to innocuous stimuli (tactile allodynia) that is nearly always resistant to known treatments such as non-steroidal anti-inflammatory drugs or even opioids. It has been reported that some antidepressants are effective for treating neuropathic pain. However, the underlying molecular mechanisms are not well understood. We have recently demonstrated that blocking P2X4 receptors in the spinal cord reverses tactile allodynia after peripheral nerve injury in rats, implying that P2X4 receptors are a key molecule in neuropathic pain. We investigated a possible role of antidepressants as inhibitors of P2X4 receptors and analysed their analgesic mechanism using an animal model of neuropathic pain.ResultsAntidepressants strongly inhibited ATP-mediated Ca2+ responses in P2X4 receptor-expressing 1321N1 cells, which are known to have no endogenous ATP receptors. Paroxetine exhibited the most powerful inhibition of calcium influx via rat and human P2X4 receptors, with IC50 values of 2.45 microM and 1.87 microM, respectively. Intrathecal administration of paroxetine produced a striking antiallodynic effect in an animal model of neuropathic pain. Co-administration of WAY100635, ketanserin or ondansetron with paroxetine induced no significant change in the antiallodynic effect of paroxetine. Furthermore, the antiallodynic effect of paroxetine was observed even in rats that had received intrathecal pretreatment with 5,7-dihydroxytryptamine, which dramatically depletes spinal 5-hydroxytryptamine.ConclusionThese results suggest that paroxetine acts as a potent analgesic in the spinal cord via a mechanism independent of its inhibitory effect on serotonin transporters. Powerful inhibition on P2X4 receptors may underlie the analgesic effect of paroxetine, and it is possible that some antidepressants clinically used in patients with neuropathic pain show antiallodynic effects, at least in part via their inhibitory effects on P2X4 receptors.

Project description:BackgroundPain is a common symptom among cancer patients and directly affects their prognosis. As the leading drug for pain management, opioids are widely prescribed. So it is necessary to get people a correct understanding and application of opioids. In order to examine whether the use of high-dose opioids might affect survival and quality of life, this retrospective cohort study was performed to explore the outcomes of patients receiving high-dose opioids for pain management in a first-class tertiary hospital in China.MethodsWe retrospectively searched medical records of inpatients and outpatients with pain who were treated with opioids in The First Affiliated Hospital, Zhejiang University School of Medicine from July to December 2021. Forty-three cases who were treated with high-dose opioids meeting inclusion criteria. Among these patients, 37 had cancer pain and 6 had neuropathic pain. All patients had regular follow-up when readmission until to April 7, 2022. Medical records of patients on high-dose opioids (equivalent to morphine ≥300 mg/d) was collected, including numerical rating scale (NRS), Karnofsky performance score (KPS), survival and adverse drug reactions (ADRs). Pain relief, quality of life, survival, and ADRs of patients after pain treatment were analyzed and evaluated.ResultsThe NRS score was significantly reduced and pain was relieved after high-dose opioid treatment. The before and after average NRS score of cancer pain was 5.2±1.6 vs. 2.2±1.1 points (P<0.001), neuropathic pain was 5.0±2.2 vs. 1.3±1.2 points (P<0.05), respectively. Although there is no statistical difference, quality of life showed a trend of improvement compared with before treatment. The before and after average KPS scores of cancer pain patients was 55.7±17.3 vs. 62.4±20.0, and neuropathic pain patients was 71.7±9.0 vs. 83.3±4.7. There were no intolerable ADRs. The median survival time was 238 days and 83 days in patients with cancer pain who received high-dose opioids and ultra-high dose opioids (equivalent to morphine ≥600 mg/d).ConclusionsMultimodal high-dose opioid pain treatments are important approaches to effectively relieve moderate to severe pain and improve the quality of life of patients. This study provides a clinical basis for future pain treatment with high-dose opioids.

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Tetrodotoxin, a Potential Drug for Neuropathic and Cancer Pain Relief?

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Tetrodotoxin, a Potential Drug for Neuropathic and Cancer Pain Relief?

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