Conduction Failure Of C Fibers In Diabetic Neuropathic Rats

For a long time axon has been considered as a cable between neurons,transmitting information from the cell body to the nerve terminal faithfully. By alarge number of fibers, ramifications and synapse, neurons are not only connectedwith each other but also with their receptors, thus constituting a complicatedneural signal processing system.However, more and more recent studies indicate that fibers are not only as a"cable"that transmits information faithfully, which make us to re-examine thefunctions of fibers, especially for the unmyelinated C fibers. It is shown thatunmyelinated C fibers exhibit obvious activity-dependent conduction, that is, theprevious action potential (AP) can affect the following AP, which induces somechanges in conduction velocity. The interspike intervals (ISI) will be altered whenthe nerve fiber is given a short pulse stimulus. The C fibers occur to conductionfailure in response to a high-frequency electrical stimulation. These resultssuggest that axons have the ability to integrate and process the afferent information along the axons during the conduction. Diabetic neuropathic ratsexhibit peripheral and central sensitization. Is it related to conduction failure of Cfibers? Three questions in the following are to be answered: (1) Whether dodiabetic neuropathic rats exhibit high-frequency firing which representhyperalgesia? (2) What properties do these high-frequency firing C fibers have?(3) What do the factors mediate the occurrence and regulation of conductionfailure? Here we try to determine these questions and provide new evidence forthe conduction failure.In the present study we used the coccygeal nerve of normal and diabetic ratsto record the single afferent C fibers in vivo. The change and characteristicsconduction failure of C fibers induced by mechanical and/or electrical stimulationwith different frequency was observed and analyzed. Furthermore, we alsoexplored the dominant factors for regulating the conduction failure.MaiMain results:1. The ratio of random blood glucose higher than 16.7 mmol/L reached 91.7% at48 h after STZ injection. The level of blood sugar in diabetic group(n=24)was significantly higher than that of control group (n=24) at 48 h, 4 w afterSTZ injection. The 50% paw withdraw threshold (PWT) began to decrease at7 d after STZ injection and was significant lower in diabetic group than thatin control group from 14~28 d. In addition, the 50% PWT for diabetic groupsignificantly decreased to 7.0±0.5% at 14 d and further decreased to 4.3±0.6% at 21 d and 2.8±0.5% at 28 d. While the 50% PWT for control groupwas almost stable at the corresponding time point (ranged from 9.9±0.5% to11.6±0.6%). The animals we chose in this experiment are 3-4 w after theinjection of STZ, which belongs to the early diabetic mellitus model. 2. There was significant difference in response to sustained suprathresholdmechanical stimulation between control and diabetic C fibers. The total of Cfibers we examined for diabetic group was 27. 10 out of 27 exhibitedhigh-frequency firing and the average number of firing was 285±28/min,while the other 17 fibers displayed lower firing frequency and the averagenumber of firing was 107±10/min. In contrast, none of 31 C fibers weexamined showed high-frequency firing and the average number of firing wasonly 82±6/min. The number of firing was significantly higher in diabetichigh-frequency (Diabetic-Hi) group than in diabetic low-frequency andcontrol group, while it was not significantly different between diabeticlow-frequency and control group.3. The conduction failure of C fibers occurred in frequency-dependent manner,that is, the higher the electrical stimulation frequency, the greater the degreeof conduction failure. The numbers of conduction failure in Diabetic-Hi Cfibers was significantly less than in control fibers in response to the sameelectrical stimulation frequency. The average initial conduction velocity ofDiabetic-Hi was 0.88±0.09 m/s, significantly higher than that of control Cfibers (0.67±0.02 m/s). The degree of conduction velocity slowing (CVs) wassignificantly different between Diabetic-Hi and control C fibers. The degreeof CVs was 9.48±1.71% for Diabetic-Hi C fibers and 15.57±2.23% forcontrol fibers.4. Low dose TTX, a blocker of persistent sodium current, can enhanceconduction failure for Diabetic-Hi C fibers in dose-dependent (5, 20, 100 nM)manner. 10 out of 17 C fibers we examined showed the above phenomenon,5. Topically applyingα-DTX, a blocker of low threshold potassium channels, toC fibers (0.5 nM) can abolish the conduction failure of normal C fibers under 5 Hz electrical stimulation, and the initial conduction velocity of C fibers wasfaster after the application ofα-DTX. The conduction failure and conductionvelocity was recovered again after washout ofα-DTX. We examine the effectofα-DTX on 5 C fibers and all of them showed the above results.ConclusionsConclusions:1. We established a new index for measuring the degree of conduction failure,that is, the percentage of conduction failure.2. The conduction failure of C fibers occurred at the main axon.3. The degree of conduction failure of diabetic high-firing frequency C fibersdecreased, so did the extent of activity-dependence.4. Persistent sodium channels and low threshold potassium channels mayinvolved in regulating the conduction failure induced by the repetitivestimulation.