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.

Dorsal root ganglion-derived exosomes deteriorate neuropathic pain by activating microglia via the microRNA-16-5p/HECTD1/HSP90 axis

“…Traditionally, glia, composed of astrocytes, oligodendrocytes, ependymocytes, and microglia, were disregarded as the structural support across the brain and spinal cord, in striking contrast to neurons, always considered critical players in CNS functioning [ 21 ]. DRG is one of the most critical structures in sensory signaling and regulation, along with pain transmission [ 22 ]. Simeoli et al .…”

Diabetic Neuropathic Pain: Directions for Exploring Treatments

“…It is of paramount importance for more and larger (especially multinational) randomised trials to be carried out in order to assess the feasibility of applying different non-pharmacological interventions against DNP into clinical practice worldwide (either individually or as supplementations to traditional therapies). In addition, the new-rising nanotechnology (e.g., nanoscale materials such as nanoparticles which can be integrated with drugs to attenuate internal oxidative stress) also highlighted its usefulness for targeting DRG in alleviating diabetic neuropathic pain [ 73 , 74 ].…”

Excitatory and inhibitory neuronal signaling in inflammatory and diabetic neuropathic pain

“…Diabetes is a complex disease associated with secondary nerve injury, chronic inflammatory processes and additional metabolic dysregulation occurring to different extents in patients, leading to a wide variety of clinical symptoms. Pain from diabetic neuropathy has been found associated with hyperglycemia in long-term diabetic patients, and linked to upregulation of voltage-gated dorsal root Na-channels (Bhandari et al 2021 ). In a murine model of type 2 diabetes with hyperglycemia induced by a high-fat diet, mechanical allodynia was observed, which correlated with an increase in inflammatory macrophages and cytokines (Saika et al 2019 ).…”