Novel Nanotechnological Approaches for Targeting Dorsal Root Ganglion (DRG) in Mitigating Diabetic Neuropathic Pain (DNP)

Abstract

Diabetic neuropathy is the most entrenched complication of diabetes. Usually, it affects the distal foot and toes, which then gradually approaches the lower part of the legs. Diabetic foot ulcer (DFU) could be one of the worst complications of diabetes mellitus. Long-term diabetes leads to hyperglycemia, which is the utmost contributor to neuropathic pain. Hyperglycemia causing an upregulation of voltage-gated sodium channels in the dorsal root ganglion (DRG) was often observed in models of neuropathic pain. DRG opening frequency increases intracellular sodium ion levels, which further causes increased calcium channel opening and stimulates other pathways leading to diabetic peripheral neuropathy (DPN). Currently, pain due to diabetic neuropathy is managed via antidepressants, opioids, gamma-aminobutyric acid (GABA) analogs, and topical agents such as capsaicin. Despite the availability of various treatment strategies, the percentage of patients achieving adequate pain relief remains low. Many factors contribute to this condition, such as lack of specificity and adverse effects such as light-headedness, languidness, and multiple daily doses. Therefore, nanotechnology outperforms in every aspect, providing several benefits compared to traditional therapy such as site-specific and targeted drug delivery. Nanotechnology is the branch of science that deals with the development of nanoscale materials and products, even smaller than 100 nm. Carriers can improve their efficacy with reduced side effects by incorporating drugs into the novel delivery systems. Thus, the utilization of nanotechnological approaches such as nanoparticles, polymeric nanoparticles, inorganic nanoparticles, lipid nanoparticles, gene therapy (siRNA and miRNA), and extracellular vesicles can extensively contribute to relieving neuropathic pain.

Keywords: diabetic neuropathic pain (DNP); dorsal root ganglion (DRG); extracellular vesicles; ligand-based targeting; nanoparticles; nanotechnology; siRNA.

Graphical Abstract

Nanotechnology based strategies has been extensively studied for their potential application in improving the delivery of drugs mitigating neuropathic pain to the targeted area with enhanced action. This review has comprehensively summarized and critically discussed the application of various novel nanotechnological approaches for mitigating diabetic neuropathic pain specifically targeting DRG.

Figure 1

Sectional organization of the spinal cord showing the dorsal root ganglion.

Figure 2

Pathophysiology of diabetic neuropathic pain. 1) Hyperglycemia stimulates the polyol pathway, which leads to the destruction of sodium currents. 2) Na⁺ channels were repeatedly opened due to sensory neurons of DRG, thus leading to increased sodium ions intracellularly. 3) As a result of polarization, there is the further opening of calcium channels. 4) In the presynaptic zone, glutamate causes activation of NMDA receptors and enhances the entry of calcium. Due to increased calcium levels, this triggers more calcium release from mitochondrial stores. 5) Activation of protein kinase C takes place due to increased calcium levels. 6) Transient receptor potential vanilloid (TRPV) phosphorylation and activation occur via protein kinase C due to which sensory neurons become hyperresponsive and also there is ROS and nitrogen radical generation, which causes cellular toxicity. 7) After the opening of mPTPs, there is the release of cytochrome C, 8) which initiates apoptotic avalanche with activation of caspases leading to sensory neuronal destruction 9) and finally leads to apoptosis. 10) Epidermis may lose some Aδ and C fibers, which causes hyperresponsiveness of various nociceptors. Inflammatory mediators such as IL-1, IL-6, and TNF-α are also involved in this process and play an essential role in developing neuropathic pain. DRG, Dorsal Root Ganglion; NMDA, N-methyl-D-aspartate; TRPV, Transient Receptor Potential Vanilloid; ROS, Reactive Oxygen Species; mPTP, mitochondrial permeability transition pores; IL-6 & IL-1, Interleukin 1 & 6; TNF-alpha, Tumour Necrosis Factor-alpha.

Figure 3

Neuropathic pain-relieving molecular mechanism of siRNA-based nanocarriers. 1) Either passive or active targeting allows the siRNA delivery device to penetrate the cell. The attachment of antibodies or aptamers, which improve the device’s specificity, aids in active targeting. 2) The siRNA nanocarrier then enters the cell. 3) There is the engulfment of the delivery device by the endosome. 4) As a result, the outer carrier breaks down, releasing free siRNA therapeutics. 5) An RNA-induced silencing complex (RISC) is formed due to the siRNA formation. 6) To progress the knockdown of the chosen mRNA, the mRNA and siRNA interact with one another. 7) The RISC cleaves the mRNA to silence proteins implicated in neuropathic pain disease. 8) P2X7 receptor expression in the dorsal root ganglion, GluN2B peptide, and the calcitonin gene-related peptide in the spinal cord are suppressed. The siRNA delivery device reduces neuropathic pain by inhibiting excitation transmission through the P2X3 receptor in the DRG and inhibiting expressed calcitonin gene-related peptide in the spinal cord, which changes the calcium-augmented pathways in neuropathic pain.