20.2.3.2 Anticonvulsants

Pregabalin is a GABA structural derivative (McClelland et al. 2004). It’s binding to

α2δ-1 subunit of voltage-gated calcium channels linked to the antinociceptive

Fig. 20.1 Pathogenesis of diabetic neuropathic pain (DNP). (1) Hyperglycemia leads to the

activation of the polyol pathway that further leads to impairment of Na⁺ currents. (2) Sensory

neurons of DRG increase the opening frequency of Na⁺ channels and also prolonged duration of

opening to increase intracellular sodium ion levels. (3) Polarizations will further cause the opening

of calcium channels. (4) Furthermore, pronounced NMDA receptor activation due to glutamate

presence in the presynaptic zone causes more influx of calcium. Increased cytosolic calcium causes

more calcium to be released from intercellular stores, particularly mitochondria. (5) Increased

calcium can cause many secondary changes like activation of protein kinase C. (6) Protein kinase

C phosphorylates and activates transient receptor potential vanilloid (TRPV), which causes sensory

neurons to become hyperresponsive, as well as the production of ROS and nitrogen radicals, which

causes cytotoxicity in neuronal cell bodies. (7) Cytochrome C released by mitochondrial mPTP

pores after its opening to start (8) apoptotic cascades with activation of caspases to cause sensory

neuronal damage (9) and cause apoptosis. (10) The epidermis may lose A fibers and C fibers and

some nociceptors resulting in a hyperresponsive state of remaining nociceptors. Inflammatory

mediators like TNF-α, IL-1, and IL-6, which are produced by glial cells of DRG, are also involved

in this cascade, acting on cytokine receptors present on the sensory neurons to induce changes such

as PKC (protein kinase C) and MAP (mitogen-activated protein) kinase activation, which play an

important role in the development of neuropathic pain

20

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

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