Mechanically-evoked C-fiber activity in painful alcohol and AIDS therapy neuropathy in the rat

Abstract

While altered activities in sensory neurons were noticed in neuropathic pain, caused by highly diverse insults to the peripheral nervous system, such as diabetes, alcohol ingestion, cancer chemotherapy and drugs used to treat AIDS, other infections and autoimmune diseases, as well as trauma, our understanding of how these various peripheral neuropathies manifest as altered neuronal activity is still rudimentary. The recent development of models of several of those neuropathies has, however, now made it possible to address their impact on primary afferent nociceptor function. We compared changes in mechanically-evoked C-fiber activity, in models of painful peripheral neuropathy induced by drinking ethanol (alcohol) or administering 2',3'-dideoxycytidine (ddC), a nucleoside reverse transcriptase inhibitor for AIDS therapy, two co-morbid conditions in which pain is thought to be mediated by different second messenger signaling pathways. In C-fiber afferents, ddC decreased conduction velocity. In contrast, alcohol but not ddC caused enhanced response to mechanical stimulation (i.e., decrease in threshold and increase in response to sustained threshold and supra-threshold stimulation) and changes in pattern of evoked activity (interspike interval and action potential variability analyses). These marked differences in primary afferent nociceptor function, in two different forms of neuropathy that produce mechanical hyperalgesia of similar magnitude, suggest that optimal treatment of neuropathic pain may differ depending on the nature of the causative insult to the peripheral nervous system, and emphasize the value of studying co-morbid conditions that produce painful peripheral neuropathy by different mechanisms.

Figure 1

Mean conduction velocities (0.86 ± 0.03, 0.76 ± 0.04, 0.72 ± 0.03 m/sec) of C-fibers from the three groups of rats (i.e., naive, ethanol (EtOH) and ddC, respectively) were significantly different (one way ANOVA, p < 0.05). The conduction velocity of C-fibers from the ddC group (n = 18) was significantly lower than that of control rats (n = 38, p < 0.05) while the conduction velocity was similar between EtOH (n = 15) and control groups (p > 0.05).

Figure 2

The mechanical threshold of C-fibers in the EtOH group (n = 15) was significantly lower that of control C-fibers (n = 38, p < 0.05, Mann Whitney test) while the mechanical thresholds between ddC (n = 18) and control groups were similar (p > 0.05, Mann Whitney test).

Figure 3

The mean responses to both sustained (60 sec) threshold and 10 g stimuli of ddC, EtOH and control C-fibers were significantly different (one way ANOVA, p < 0.01). The responses of EtOH group (n = 15) were significantly higher than those of control rats (n = 38, p < 0.01, Tukey's multiple comparison test) while the responses of C-fibers in the ddC group (n = 18) were similar to those of controls (p > 0.05, Tukey's multiple comparison test).

Figure 4

The ISI distributions of both EtOH (n = 15) group of C-fibers in responses to sustained (60 sec) threshold and 10 g stimuli were significantly changed. A&D, the ISI distributions of control C-fibers (n = 38) in responses to sustained threshold and 10 g stimuli, respectively. B&C, ISI 0.1–0.2 s of responses in EtOH group was significantly higher than that of controls (p < 0.05, t-test) and ISI 0.3–0.4 s of responses in ddC group (n = 18) was significantly higher than that of controls (p < 0.05, t-test). E&F, the ISI distributions of EtOH group in responses to 10 g stimulation were significantly changed while the ISI distributions of ddC group were similar to those of controls. ISI 0–0.2 s of responses in EtOH group was significantly higher than those of control animals (p < 0.01, t-test)

Figure 5

The Cv2 distribution of high firing fibers (B, n = 7) for EtOH group is markedly different from low firing fibers (C, n = 8) for EtOH group and control animals (A, n = 38) while they were similar between low firing fibers for EtOH group and controls. The Cv2 distributions were similar between ddC (D, n = 18) and controls.