ONSET OF A PAINFUL PERIPHERAL NEUROPATHY IN RAT - A PARTIAL AND DIFFERENTIAL DEAFFERENTATION AND SPONTANEOUS DISCHARGE IN A-BETA AND A-DELTA PRIMARY AFFERENT NEURONS

1. The activity of primary afferent axons was recorded in rats that had received a chronic constriction injury (CCI) to the common sciatic nerve. The CCI gives rise to a painful peripheral neuropathy that is characterized by allodynia, hyperalgesia, and, probably, spontaneous pain (or dysesthesia). In the majority of animals, these neuropathic pain symptoms begin 2 days postinjury; sciatic nerve afferents were examined just before and just after the time of symptom onset, at 1 and 3 days postinjury. 2. We used two stimulating electrodes, one proximal to the injury and the other distal, to activate the injured sciatic nerve while we recorded from individual primary afferent axons in microfilaments teased from the L4-L6 dorsal roots. Measurements of conduction velocities (calculated from the proximal electrode) and evaluation of conduction through the site of injury were made from 181 Abeta, 135 Adelta, and 60 C-fibers. 3. The percentage of axons that did not conduct through the injury site at 1 day postinjury was 85% for the Abeta fibers and 55% for the Adelta fibers, but only 9% for the C-fibers. By day 3, these percentages had increased to 89% for the Abeta fibers, 87% for the Adelta fibers, and 32% for the C-fibers. Some axons were activated from the distal stimulating electrode at currents >5- 10 times those required from the proximal electrodes, but their distally evoked responses did not have the longer latencies expected from a more distant site of activation. Control experiments confirmed that such high-threshold responses were due to current spread from the distal electrode to a site proximal to the nerve injury. 4. Spontaneous discharges were observed in 35% of Abeta fibers, 15% of Adelta fibers, and 3% of C-fibers (data from 1 and 3 days postinjury combined). Of the 55 Abeta fibers exhibiting spontaneous discharge, 89% did not conduct through the injury site; the same was true of 65% of the Adelta fibers (n = 20). Both of the two spontaneously discharging C-fibers conducted through the injury. The frequency of the spontaneous discharge of the myelinated fibers ranged from 10 to 50 Hz and was usually regular or bursting. 5. Intravenous administration of gallamine triethiodide (Flaxedil), a K+ channel blocker, either induced activity in previously silent fibers or increased the frequency of spontaneous activity in 50% (21/42) of Abeta fibers and 19% (3 /16) of Adelta fibers. There was no effect of systemic gallamine on any (0/4) of the C-fibers tested. 6. These data show that the abnormal pain sensations begin at about the same time as two abnormalities of primary afferent function. First, a large majority of Abeta and Adelta fibers become incapable of conducting impulses through the injury site, whereas a majority of the unmyelinated primary afferents conduct normally. Thus the injured nerve's peripheral territory is partially and differentially deafferented. Second, it is probable that as early as 1 day postinjury the spinal cord dorsal horn is bombarded by high levels of spontaneous discharge from many of the injured nerve's Abeta and Adelta afferents. It is possible that the high level of spontaneous input from myelinated afferents contributes to alterations in the somatosensory processing regions of the CNS. Moreover, it is probable that many spontaneously active Adelta afferents are nociceptors and that their activity results in spontaneous pain.