from the epidermis, respectively (McCarthy et al. 1995). A mitochondrial abnormal

function has a crucial role to play in the development of many disorders of the

nervous system, including neuropathic pain which is a peripheral nervous system

disorder (Bouillot et al. 2002). There are various interrelated mitochondrial-based

pathways, such as intracellular Ca²⁺ regulation (Shishkin et al. 2002), reactive

oxygen production (Chung 2004), and apoptotic signaling pathways (Joseph and

Levine 2004), which play a significant role in the development of neuropathic pain.

Neuropathic pain is not due to one independent pathway but many pathways

interrelated to one other.

Hyperglycemia seems to trigger changes in the sodium channel expression.

Upregulated sodium channels (voltage-gated) were widely seen in pain models of

neuropathy in dorsal root ganglion (DRG) (Black et al. 1999). Hyperglycemia

affects Na⁽⁺⁾ currents, possibly due to polyol pathway activation, and impairs

Na⁽⁺⁾-K⁽⁺⁾ pump (Misawa et al. 2009). These channels influence the processing of

action potential along with their transmission and can be categorized as tetrodotoxin

sensitive (TTX-S) (Roy and Narahashi 1992). In the animal models of diabetes,

many findings suggest upregulation of Nav1.3 channels which are tetrodotoxin

sensitive and have shown a role in the embryonic development stage (Felts et al.

1997) and Nav1.7 in the dorsal root ganglion (DRG) (Ogata and Ohishi 2002;

Galloway and Chattopadhyay 2013; Hong et al. 2004). DRG neurons and sensory

neurons of the dorsal horn show a rise in the frequency of opening of sodium

channels and their opening duration has also been seen to be prolonged to elevate

the levels of intracellular sodium ion. The polarization of the neuron further causes

increased opening of calcium channels and causes hyperpolarization (Misawa et al.

2009). Overexpression of α2δ-1 subunit of the calcium channel has been reported to

play a part in the oversensitivity of nociceptive responses to harmless mechanical

stimulation that is a characteristic feature of allodynia in rats in which nerves of the

spinal area are injured (Luo et al. 2002). Due to the overexpression of this subunit,

more extracellularly present calcium enters the cell that further leads to various

signaling cascades (Luo et al. 2002). Also, glutamate is released in the presynaptic

zone which causes NMDA receptors to activate. NMDA receptor activation will

again elevate the entry of extracellular calcium inside the cell (Zhou et al. 2011).

Mitochondria in response to hyperpolarization of cells start releasing more calcium

in the cytoplasm from its intercellular stores. As calcium concentration elevates

inside the cell, it leads to activation of various signaling cascades, and phosphoryla-

tion of protein kinase C is one of them (Lipp and Reither 2011), leading to

upregulation of transient receptor potential vanilloid (TRPV) (Bhave et al. 2003),

which directly causes alterations in the sensory neurons which results in hyperre-

sponsive state. Due to TRPV upregulation, nitric oxide and oxygen free radicals are

also produced and ultimately cause neuronal cytotoxicity (Fernandes et al. 2012).

TRPV1 co-reside with transient receptor potential ankyrin 1 (TRPA1) in particu-

lar neurons of DRG, and they are proven to have a role in the generation of the pain

signals and in inflammation that may occur due to various irritants like chemical

agents, ROS, or nitrogen radicals (Ta et al. 2010). Cytochrome C may be released

from the mitochondria, while permeability of mPTP pores increased due to

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

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