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  • Curcumin is the active ingredient extracted from

    2022-08-04

    Curcumin is the active ingredient extracted from the natural medicine turmeric rhizome (Goel et al., 2008, Aggarwal and Harikumar, 2009). Studies have shown that curcumin has anti-tumor, anti-inflammatory, antioxidant and antimicrobial properties (Larsen et al., 2007, López-Lázaro, 2008). Although curcumin is non-toxic and has small side effects (Dickinson et al., 1992, Chu et al., 2013), the use of curcumin is limited due to its poor metabolism stability in vivo and low bioavailability (Anand et al., 2007, Goel et al., 2008). Nanoscale drug delivery systems formulated from biocompatible and biodegradable polymers constitute an evolving approach to drug delivery (Bala et al., 2005, Lamprecht et al., 2005). Nanoparticle encapsulation of drugs can improve the drug targeting, the drug bioavailability and reduce drug toxicity side effects (Lamprecht et al., 2005, Chu et al., 2013), so the medicinal properties of nanoparticle-encapsulated curcumin can be fully utilized (Chu et al., 2013, Yang et al., 2015). In this study, we investigated the effects of nanoparticle-encapsulated curcumin on gp120-induced neuropathic pain mediated by the P2X3 receptor in rat primary afferent neurons.
    Materials and methods
    Results
    Discussion Neurotoxins and inflammatory mediators can cause hyperexcitability of the DRG neurons, leading to spontaneous or persistent firing (Richardson and Vasko, 2002, Basbaum et al., 2009). HIV-1 gp120 protein has neurotoxin properties and therefore may directly impact the excitability of DRG neurons, leading to HIV-1-associated pain (Milligan et al., 2000, Herzberg and Sagen, 2001, Wallace et al., 2007, Maratou et al., 2009, Kamerman et al., 2012, Hao, 2013). Our study indicated that the mechanical withdrawal threshold (MWT) and the thermal withdrawal latency (TWL) in the peripheral gp120 application model were decreased compared to those in the sham group. Meanwhile, our results also showed that the enhanced hyperalgesia was associated with the upregulated VX-689 of P2X3 mRNA and protein in the DRG in the HIV-1 gp120 treatment group. The P2X3 receptor is preferentially expressed on dorsal root ganglion (DRG) neurons and has been implicated in neuropathic pain hypersensitivity (Barclay et al., 2002, Ford, 2012, Burnstock, 2013). The immunoreactivity test in this study revealed that the expression levels of the P2X3 immunoreactivity in the DRG neurons was significantly increased in the gp120 group compared to the sham group. Therefore, the upregulated P2X3 receptor in the DRG neuron participated in the signal transmission of HIV-associated pain. Curcumin, a derived product from the common spice turmeric was formulated into biodegradable nanoparticles, which improved its bioavailability (Bisht et al., 2007, Shaikh et al., 2009). Our experiments showed that nano curcumin decreased the expression levels of the P2X3 receptor and relieved the MWT and TWL in the gp120-treated rats, which indicated that the nano curcumin lessened the pathological injury mediated by the P2X3 receptor in the DRG neurons in the signal transmission of HIV-associated pain. Reducing the size into nanoscale in drug carriers has many advantages. Nanoscale in drug carriers improves the pharmacokinetics and the biodistribution of therapeutic agents due to higher ratio of surface area to volume, diminishes toxicity by their preferential accumulation at the target site, facilitates intracellular delivery and prolongs their retention time (Bala et al., 2005, Bisht et al., 2007). The concentration of the nano curcumin in our experiment was only 4mg/ml for one rat, which was significantly lower than the common dose of 50mg/kg–300mg/kg. The activation of the ERK pathway is involved in the transmission of pain signaling by sensitizing primary afferents (Ji et al., 2009, Lai et al., 2011). Therefore, the blockade of ERK activation in the primary sensory neurons may decrease the mechanical hypersensitivity and the thermal hypersensitivity in inflammatory pain. The activation of the P2X3 receptor follows the activation of the ERK1/2-mediated signal transduction pathways and results in pain (Lai et al., 2011, Liu et al., 2014, Yi et al., 2017). Accompanied with the upregulated expression of the P2X3 receptor, our study also showed that the IOD ratio of p-ERK1/2 to ERK1/2 in the gp120 group was higher than in the sham group. The phosphorylation of the MAPK indicates its activation. The IOD ratios of p-ERK1/2 to ERK1/2 in the gp120 plus nano curcumin-treated rats significantly decreased compared to the gp120 group. Our studies indicated that the nano curcumin inhibited both the upregulation of the P2X3 receptor and the phosphorylation of ERK1/2 in the DRG of the gp120-treated rats. Therefore, nano curcumin treatment decreased the upregulated expression of the P2X3 receptor and lowered the activation of ERK1/2 in the DRG to reduce the mechanical hyperalgesia and thermal hyperalgesia in gp120-treated rats.