involved in the transmission of pain signals (Burnstock 2006, 2007; Tsuda et al.

2010; Liang et al. 2010; Zhang et al. 2010). Pain management in PDN is done via the

antidepressant agents such as duloxetine, GABA analogues, opioids, and topical

drugs such as capsaicin. The FDA has approved the use of duloxetine and pregabalin

for the treatment of PDN in 2004, and tapentadol which is formulated as the

extended-release drug was approved for DNP in 2012 for long-term treatment of

this disorder where other drugs cannot be preferred (Javed et al. 2015). Currently,

available therapies do not offer to relieve pain to all the patients suffering from DNP

and are also seen to be restricted by unexpected adverse effects, such as somnolence

and dizziness, and the requirement for numerous daily doses that further reduces the

patient’s compliance. It is reported that P2X3 receptor activation leads to allodynia

in rat models of diabetes (Xu et al. 2011). DM rats when treated with

NONRATT021972 siRNA have shown that the expression of the DRG P2X3

receptor is significantly decreased as compared to T2DM rats in which no treatment

is given. Ribonucleic acid interference (RNAi) is emerging as a gene-silencing tool

that inhibits the expression of the gene after transcription that inhibits the particular

protein synthesis by activating the RNA-induced silencing complex (RISC). It is

now possible for physicians to treat a disease with the help of genes by administering

RNAi therapeutics such as siRNA to a patient to inhibit the expression of a particular

gene rather than using complex treatment strategies (Setten et al. 2019). siRNA’s

short half-life, nonfunctioning of administered siRNA due to degradation by circu-

latory RNase, as well as rapid clearance by the renal route are some of the key

difficulties complicating the clinical translation of siRNA therapeutics (Youngren

et al. 2013; Tekade et al. 2015). Efficient nanocarriers should ensure evasion from

immunogenic recognition and clearance through our reticuloendothelial system.

Serum proteins like albumin and IgG tend to interact with siRNA cationic bodies,

leading to the enhanced size of the complex. This ultimately lessens the targeted

siRNA fraction that reaches the target site (Zhao and Feng 2015). Attaching a ligand

entity like an antibody, aptamer, or peptide provides specificity to the siRNA

molecule and ensures release at the desired site of action. Lipid nanoparticles

possessing a positive charge attributed through cation lipidic formulations are

efficient in condensing the genes and ensuring uptake by the cell (Ozpolat et al.

2014). In the following chapter, siRNA-encapsulated nanoparticles for targeting

dorsal root ganglion with the paradigm of diabetic neuropathic pain are discussed.

20.2

Diabetic Neuropathic Pain: An Unmet Medical Need

20.2.1 Epidemiology

Diabetic neuropathy, with various anatomic characteristics, clinical courses, and

phenotypes, includes a series of clinical complex disorders that affect the central

nervous system (Martin et al. 2014). Diabetic peripheral neuropathy (DPN) and its

incidence rise with the duration of diabetes. Diabetes has now become an epidemic

globally; nearly 463 million adults in the age groups of 20–79 years had diabetes in

20

siRNA-Encapsulated Nanoparticles for Targeting Dorsal Root Ganglion (DRG). . .

371