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More on Peripheral Sensitization

Neurotrophic factors also play an important role in peripheral sensitization. After peripheral nerve injury, the physiology of the nerve itself can become altered. Nerve injury can stimulate nerve growth factor (NGF) expression. NGF promotes the growth and repair of nerves. Satellite glial cells in the DRG synthesize more NGF when needed. Mast cells and fibroblasts release NGF as well. NGF binds to tyrosine kinase (TrkA) on A6 and C fibers which activates these primary afferent terminals by upregulating Nav channels.4

In peripherally injured nerves, increased densities of Nav channels can be noted which can result in increased spontaneous discharges of the nerve. Independent pacemakers have been noted in surgically damaged nerves. Increased expressions of receptors along an injured axon have also been noted which can result in increased sensitivity.4 Peripheral nerve transection results in the formation of neuromas. These neuromas are sensitized by immune activation by cytokines such as TNF (as previously described). Both A and C fibers show ectopic activity. The autonomic nervous system impacts the damaged nerve as well. Postganglionic sympathetic efferents sprout into the nerve injury site as well, further sensitizing the nerve in response to catecholamine release. The postganglionic terminals are influenced by nerve growth factor released from local Schwann cells to release catecholamines which excite the injured nerve and the nerve’s dorsal root ganglia (DRG). Prostanoids also enhance the opening of TTX-insensitive sodium channels on the afferent terminals.28

Injured tissue is noted to have a lower pH and higher K+ concentration compared to non-injured tissue. Channels present on C fibers are activated by higher H+ concentrations. TRPVl/acid-sensing ion channels (ASICs) are just one example.28

The primary afferents themselves are also noted to play a role in the local inflammatory milieu. CGRP and SP are released from the peripheral terminals of the C fibers. CGRP and SP result in vasodilation, plasma extravasation, and degranulation of mast cells. This leads to the previously mentioned reddening and swelling.

During primary sensitization, intracellular signaling pathways such as the activation of protein kinase A (PKA)29 and protein kinase С (PKC)30 result in the phosphorylation and resultant activation of receptors such as TRPVl. The action of prostaglandin is also noted to upregulate PKA which also activates Na,, 1.8 and 1.9 channels.31 Both of these intracellular alterations result in increased afferent activation. Extracellular pathways can also become activated. Phosphatidyl inositol-3 kinase (PI3K), activated via an extracellular signal-regulated kinase (ERK)-dependent manner, can also sensitize TRPVl.32-33

It is important to note that while primary sensitization occurs peripherally, central mechanisms via the endocrine system can play an important role. Stressors can activate the hypothalamus to direct the pituitary to secrete adrenocorticotropic hormone (ACTH), macrophage migration inhibitory factor (MIF), and pituitary adenylate cyclase-activating polypeptide (PACAP). ACTH stimulates the release of cortisol and norepinephrine from the adrenal glands which act on and modulate the immune system (lymphocytes, granulocytes, and macrophages). The immune cells secrete cytokines, chemokines that modulate inflammatory responses in the skin. Skin inflammation has a reciprocal effect on the immune cells via cytokines, chemokines, prostaglandins, leukotrienes, nitric oxide, and melanocyte-stimulating hormone impacting the production of inflammatory mediators such as cytokines.34

DRG

The primary afferent summarizes the nociceptive information from the periphery and feeds this information centrally toward the spine where the signal passes through the primary afferent cell body—the dorsal root ganglia (DRG). The DRG is yet another location where nociceptive information can be modulated. The DRG is impacted by repetitive stimulation and adjusts gene transcription. The DRG synthesizes modulatory neuropeptides that are rapidly transported antegrade and retrograde, impacting the sensitivity of the nociceptor.28 Within the DRG, multiple cell bodies are encased in a small region. These cell bodies can pathologically cross-talk. This short circuit process is known as ephaptic-transmission and results in increased excitation32 and pain outside of the originally injured location. Ephaptic-transmission can also occur in the periphery in the case of peripheral neuromas. A large low-threshold fiber such as an A|3 fiber can create activation in a high- threshold fiber such as an A6 fiber—essentially turning innocuous information into nociception.

The cell bodies of the DRG are surrounded by small glial cells (SGCs) that support and supply nutrients to these cell bodies via gap junctions. In the presence of induced inflammation, there is increased gap junction coupling and boosting of neuronal excitability. This can further drive the pain sensation beyond the field of injury. Pro- and anti-inflammatory cytokines create a milieu that influences the interaction. In cases of chronic pain, these interactions can fail to resolve themselves.4

 
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