Reduced conduction failure of the main axon of polymodal nociceptive C-fibres contributes to painful diabetic neuropathy in rats

Abstract

Painful diabetic neuropathy is a common complication of diabetes mellitus and can affect many aspects of life and severely limit patients' daily functions. Signals of painful diabetic neuropathy are believed to originate in the peripheral nervous system. However, its peripheral mechanism of hyperalgesia has remained elusive. Numerous studies have accumulated that polymodal nociceptive C-fibres play a crucial role in the generation and conduction of pain signals and sensitization of which following injury or inflammation leads to marked hyperalgesia. Traditionally, the number of nociceptive primary afferent firings is believed to be determined at the free nerve endings, while the extended main axon of unmyelinated C-fibres only involves the reliable and faithful propagation of firing series to the central terminals. We challenged this classic view by showing that conduction of action potential can fail to occur in response to repetitive activity when they travel down the main axon of polymodal nociceptive C-fibres. Quantitative analysis of conduction failure revealed that the degree of conduction failure displays a frequency-dependent manner. Local administration of low threshold, rapidly activating potassium current blocker, α-dendrotoxin (0.5 nM) and persistent sodium current blocker, low doses of tetrodotoxin (<100 nM) on the main axon of C-fibres can reciprocally regulate the degree of conduction failure, confirming that conduction failure did occur along the main axon of polymodal nociceptive C-fibres. Following streptozotocin-induced diabetes, a subset of polymodal nociceptive C-fibres exhibited high-firing-frequency to suprathreshold mechanical stimulation, which account for about one-third of the whole population of polymodal nociceptive C-fibres tested. These high-firing-frequency polymodal nociceptive C-fibres in rats with diabetes displayed a marked reduction of conduction failure. Delivery of low concentrations of tetrodotoxin and Nav1.8 selective blocker, A-803467 on the main axon of C-fibres was found to markedly enhance the conduction failure in a dose-dependent manner in diabetic rats. Upregulated expression of sodium channel subunits Nav1.7 and Nav1.8 in both small dorsal root ganglion neurons and peripheral C-fibres as well as enhanced transient and persistent sodium current and increased excitability in small dorsal root ganglion neurons from diabetic rats might underlie the reduced conduction failure in the diabetic high-firing-frequency polymodal nociceptive C-fibres. This study shed new light on the functional capability in the pain signals processing for the main axon of polymodal nociceptive C-fibres and revealed a novel mechanism underlying diabetic hyperalgesia.

Gabapentin reduces allodynia and hyperalgesia in painful diabetic neuropathy rats by decreasing expression level of Nav1.7 and p-ERK1/2 in DRG neurons

“…The data indicated that Nav1.7 was increased in diabetic neurons compared with controls, and the increases were also shifted accordingly in diabetic animals. These results were similar to the previous report that showed altered Na þ currents in diabetic neuropathy (Sun et al, 2012). Furthermore, GBP not only reduced Nav1.7 but also largely reversed the changes for activation of p-ERK1/2.…”

“…And the continuous GBP injection has been proven to be valid measures in our study. Many studies have reported altered excitability in DRG neurons, including small, medium and large neurons from a chronic compression disease (CCD) model and STZ-induced model (Huang and Song, 2008;Villiere and McLachlan, 1996;Sun et al, 2012;Tan et al, 2006). Similarly, our data demonstrated that DRG neurons from diabetic rats increase the excitability of neurons compared with the control.…”

“…Voltage-dependent sodium channels are important regulators of excitability in neurons and play a key role in action potentials. This enhanced sodium current is strongly supported by the up-regulated expression of sodium channel subunits Nav1.7 in both small DRG neurons and sodium current is significantly increased in small-sized DRG neurons in streptozotocin (STZ)-induced diabetic rats (Hong et al, 2004;Sun et al, 2012). Indeed, some study has shown that Nav1.7 can mediate the expression of ERK1/2 and activation of p-ERK1/2 contributed to the excitability of DRG neurons (Persson et al, 2011;Stamboulian et al, 2010;Lin et al, 2011).…”

Colonic Hypersensitivity and Sensitization of Voltage-gated Sodium Channels in Primary Sensory Neurons in Rats with Diabetes

“…Sodium channel α-subunits Na V 1.7 and Na V 1.8 are the 2 major subunits expressed by dorsal root ganglion neurons and are thought to play an important role in peripheral neuropathy in STZ-induced diabetic rats. 42 Here, we showed for the first time that STZ injection increased expression of Na V 1.7 and Na V 1.8 in DRGs. This is in agreement with previous reports that VGSCs have important roles in nociception and visceral pain.…”

Docosahexaenoic acid inhibits mechanical allodynia and thermal hyperalgesia in diabetic rats by decreasing the excitability of DRG neurons

“…It has been reported that abnormal hyperexcitability of primary sensory neurons contributed to the exaggerated pain associated with diabetic neuropathy (Hong et al, 2004a;Sun et al, 2012a;Jackson and Bean, 2007). It has been shown that Nav1.7 and Nav1.8 were over-expressed and the transient sodium current was increased significantly in small dorsal root ganglion (DRG) neurons in streptozotocin (STZ)-induced diabetic rats (Hong et al, 2004a;Sun et al, 2012a).…”