Keywords

Diabetic neuropathic pain (DNP) · Dorsal root ganglion (DRG) · siRNA

20.1

Introduction

Diabetic neuropathy is a well-established outcome of diabetes that affects nearly

90% of diabetic patients (Boulton et al. 2005). Diabetes has now become an

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

diabetes in 2019, and this number is projected to rise to 700 million by 2045

(International Diabetes Foundation 2019). Distal symmetric polyneuropathy

(DSPN) is the most well-known diabetic neuropathy (Tesfaye et al. 2013). The

distal part of the foot and toes is typically affected by DSPN but progresses gradually

towards the legs. The progressive loss of nerve fibers is one of the most common

consequences of it that leads to diabetic retinopathy or nephropathy, affecting both

the autonomic nervous system and somatic divisions (Tesfaye et al. 2013). Ulcers on

the foot and debilitating neuropathy are the main clinical complications with greater

morbidity and mortality (Boulton et al. 2004). Diabetic neuropathic pain is

characterized by prickling or burning sensations (Cobos-Palacios et al. 2020). It

usually gets worse during nights that lead to poor sleep. This pain can be persistent

and followed by epidermic allodynia, which majorly affects the quality of life of

patients and impairs their capabilities to perform daily activities (Quattrini and

Tesfaye 2003). Several hypotheses are suggested to justify the pain in diabetic

neuropathy like changes in the nerves present peripherally, changes in the expression

of sodium and calcium channel, and metabolic and autoimmune disorders caused by

glial cell activation (Tesfaye et al. 2013). More recently, core pain pathways have

been observed, such as facilitator/inhibitor descending pathway imbalance and an

increase in thalamic vascularity and (Tesfaye et al. 2013). It has been known from

many studies that dorsal root ganglion (DRG) neurons are one of the specific targets

and may contribute to major complications of diabetic neuropathy, as chronic

hyperglycemia results in radiculopathy and distal sensory neuropathy associated

with vacuolar ganglionopathy (Kishi et al. 2002). There is a major clinical applica-

tion of the dorsal root ganglion (DRG), especially in its connection with diabetic

neuropathic pain. DRG neurons arise from the dorsal root of the spinal nerves,

bringing sensory signals to the central nervous system for a response from different

receptors, including those for pain and temperature (Ahimsadasan and Kumar 2018).

Until recently, the dorsal root ganglion has been regarded as a passive organ that

serves functions and pathways between the PNS and CNS metabolically. However,

recent findings indicate that DRG is an active participant in peripheral processes,

including PAF damage, inflammation, and the production of neuropathic pain

(Ahimsadasan and Kumar 2018). A lesion or disorder of peripheral neuropathic

pain is peripherally originated by the somatic nervous system. Peripheral damage to

the nerves in neuropathic pain leads to overexpression of the P2X3 receptor in the

DRG. The P2X3 receptor is expressed primarily in DRG neurons and is seen to be

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R. Bhandari et al.