Zinc Inhibits TRPV1 to Alleviate Chemotherapy-Induced Neuropathic Pain

Abstract

Zinc is a transition metal that has a long history of use as an anti-inflammatory agent. It also soothes pain sensations in a number of animal models. However, the effects and mechanisms of zinc on chemotherapy-induced peripheral neuropathy remain unknown. Here we show that locally injected zinc markedly reduces neuropathic pain in male and female mice induced by paclitaxel, a chemotherapy drug, in a TRPV1-dependent manner. Extracellularly applied zinc also inhibits the function of TRPV1 expressed in HEK293 cells and mouse DRG neurons, which requires the presence of zinc-permeable TRPA1 to mediate entry of zinc into the cytoplasm. Moreover, TRPA1 is required for zinc-induced inhibition of TRPV1-mediated acute nociception. Unexpectedly, zinc transporters, but not TRPA1, are required for zinc-induced inhibition of TRPV1-dependent chronic neuropathic pain produced by paclitaxel. Together, our study demonstrates a novel mechanism underlying the analgesic effect of zinc on paclitaxel-induced neuropathic pain that relies on the function of TRPV1. The chemotherapy-induced peripheral neuropathy is a major limiting factor affecting the chemotherapy patients. There is no effective treatment available currently. We demonstrate that zinc prevents paclitaxel-induced mechanical hypersensitivity via inhibiting the TRPV1 channel, which is involved in the sensitization of peripheral nociceptors in chemotherapy. Zinc transporters in DRG neurons are required for the entry of zinc into the intracellular side, where it inhibits TRPV1. Our study provides insight into the mechanism underlying the pain-soothing effect of zinc and suggests that zinc could be developed to therapeutics for the treatment of chemotherapy-induced peripheral neuropathy.

Nrf2 activation ameliorates mechanical allodynia in paclitaxel-induced neuropathic pain

“…As a frontline chemotherapeutic agent, paclitaxel often leads to the occurrence of PINP, which may result in the discontinuation of chemotherapy [ 25 , 26 ]. In addition, PINP usually persists long after the cessation of paclitaxel treatment, and is unfortunately refractory to commonly used analgesic strategies; thus, it affects the quality of life of cancer patients [ 27 , 28 ].…”

Paclitaxel Induces Upregulation of Transient Receptor Potential Vanilloid 1 Expression in the Rat Spinal Cord

“…TRPV1 receptors could play a pivotal role in the modulation of nociceptive signaling in inflammatory pain [ 33 ]. TRPV1 is known to play an important role in peripheral neuropathic pain induced by chemotherapeutic drugs [ 10 , 20 , 34 ]. Thus, TRPV1 receptors in the spinal cord might be activated by PTX treatment.…”

“…Recent evidence suggests that transient receptor potential vanilloid 1 plays a crucial role in PTX-induced painful neuropathy. Rodent models of PTX-induced peripheral neuropathy were developed to elucidate the pain mechanisms caused by PTX treatment [ 7 , 8 , 9 , 10 ]. Neurophysiological and biochemical studies show that the activation and sensitization of nociceptors plays a key role in neuropathic pain behavior following PTX treatment [ 11 , 12 , 13 ].…”

Electroacupuncture Alleviates Paclitaxel-Induced Peripheral Neuropathic Pain in Rats via Suppressing TLR4 Signaling and TRPV1 Upregulation in Sensory Neurons

“…It is activated by a variety of noxious stimuli, such as capsaicin, protons, noxious heat, and some endogenous-inflammation-associated lipid metabolites, and therefore generates pain signal upon activation [12,13,14]. TRPV1 expression is upregulated in dorsal root ganglion (DRG) neurons of rats treated with paclitaxel, whereas TRPV1 antagonists significantly reduced pain hypersensitivities, suggesting that TRPV1 makes major contributions to paclitaxel-induced neuropathic pain symptoms [15,16,17,18].…”