Temporal regularity determines the impact of electrical stimulation on tactile reactivity and response to capsaicin in spinally transected rats

Abstract

Nociceptive plasticity and central sensitization within the spinal cord depend on neurobiological mechanisms implicated in learning and memory in higher neural systems, suggesting that the factors that impact brain-mediated learning and memory could modulate how stimulation affects spinal systems. One such factor is temporal regularity (predictability). The present paper shows that intermittent hindleg shock has opposing effects in spinally transected rats depending upon whether shock is presented in a regular or irregular (variable) manner. Variable intermittent legshock (900 shocks) enhanced mechanical reactivity to von Frey stimuli (hyperreactivity), whereas 900 fixed-spaced legshocks produced hyporeactivity. The impact of fixed-spaced shock depended upon the duration of exposure; a brief exposure (36 shocks) induced hyperreactivity whereas an extended exposure (900 shocks) produced hyporeactivity. The enhanced reactivity observed after variable shock was most evident 60-180 min after treatment. Fixed and variable intermittent stimulation applied to the sciatic nerve, or the tail, yielded a similar pattern of results. Stimulation had no effect on thermal reactivity. Exposure to fixed-spaced shock, but not variable shock, attenuated the enhanced mechanical reactivity (EMR) produced by treatment with hindpaw capsaicin. The effect of fixed-spaced stimulation lasted 24h. Treatment with fixed-spaced shock also attenuated the maintenance of capsaicin-induced EMR. The results show that variable intermittent shock enhances mechanical reactivity, while an extended exposure to fixed-spaced shock has the opposite effect on mechanical reactivity and attenuates capsaicin-induced EMR.

Figure 1

Fixed and variable spaced stimulation have a divergent effect on tactile reactivity. (A) Subjects received a baseline (BL) assessment of reactivity using von Frey monofilaments prior to treatment with 900 variable spaced (filled circles), 900 fixed spaced legshocks (filled triangles), or no shock (Unshk; open squares). Response thresholds were then reassessed at 30, 60, and 180 min after shock treatment. The left y-axis depicts data on a linear scale based on a transformation (log10 [10,000 · g]) of the force required to bend the thinnest filament that produced paw withdrawal. The right y-axis depicts the gram force equivalents. (B) The change from baseline scores. Asterisks indicate statistically significant differences (p < .05), and error bars depict ± SEM. The inset depicts the experimental design.

Figure 2

Brief exposure to fixed spaced stimulation causes mechanical hyperreactivty, while an extended exposure causes hyporeactivity. Tactile reactivity was assessed after rats received 0, 36, 180, or 900 fixed legshocks. Assessments were made at 30, 60, and 180 min following legshock. Because time was not a significant factor in our analysis we collapsed across this variable and present mean data. (A) Mean absolute tactile thresholds after shock treatment. The left y-axis depicts linearized data while the right y-axis depicts the gram force equivalents. (B) Mean change from baseline scores. Asterisks indicate statistically significant differences (p < .05), and error bars depict ± SEM. The inset depicts the experimental design.

Figure 3

Impact of sciatic nerve stimulation depends upon both temporal regularity and time of testing. Rats were administered 900 variable (filled circles) or 900 fixed (filled triangles) spaced monophasic DC shocks to the sciatic nerve, or no shock (Unshk; open squares), and tactile reactivity was monitored over a period of 3 hr. (A) Mean absolute tactile thresholds prior to (Baseline, BL) and 0, 60, 120, and 180 min after shock treatment. The left y-axis depicts linearized data while the right y-axis depicts the gram force equivalents. (B) Mean change from baseline scores. Asterisks indicate statistically significant differences (p < .05), and error bars depict ± SEM. The inset depicts the experimental design.

Figure 4

Fixed and variable tailshock have divergent effects on tactile, but not thermal, reactivity. Following baseline assessments of tactile and thermal responding, rats were administered 900 variable (filled circles) or 900 fixed (filled triangles) tailshocks, or no shock (Unshk). (A) Mean absolute tactile scores prior to treatment (Baseline, BL) and at 0, 60, 120, and 180 min after treatment. The left y-axis depicts linearized data while the right y-axis depicts the gram force equivalents. (B) Mean change from baseline tactile scores. (C) Absolute tail-flick latencies prior to and after shock treatment. (D) Mean change from tail-flick scores. The asterisks indicate statistical significance relative to unshocked (Unshk) controls (p < .05), and error bars depict ± SEM. The inset depicts the experimental design.

Figure 5

Pretreatment with fixed, but not variable, spaced stimulation prevents capsaicin-induced EMR. Immediately following assessment of baseline tactile reactivity rats were administered 900 variable legshocks, 900 fixed spaced legshocks, or nothing (Unshk). After the impact of shock treatment on tactile reactivity was assessed (Postshock), subjects received a subcutaneous hindpaw injections of 1% capsaicin (50 μL) or saline to the dorsal surface of one hindpaw (counterbalanced). Injections and stimulation always occurred on the same limb. Tactile reactivity was re-assessed 0–60 min after treatment (Postinjection). (A–C) Tactile reactivity after shock treatment. (D–F) Tactile reactivity after saline (unfilled bars) or capsaicin (filled bars) treatment, averaged over time. In both sets of panels, data are presented for the treated leg (left), untreated leg (center), and mean tactile reactivity (right). Asterisks indicate statistically significant differences (p < .05), and error bars depict ± SEM. The inset depicts the experimental design.

Figure 6

Treatment with fixed-spaced stimulation prevents capsaicin-induced EMR when administered 24 hr prior to capsaicin. After baseline tactile reactivity was assessed, subjects received 900 fixed spaced legshocks, 900 variable shocks, or nothing (Unshk). Tactile reactivity was then re-assessed (Postshock). The next day, after tactile reactivity was measured (Preinjection), rats received a subcutaneous hindpaw injection of 1% capsaicin (50 μL) in the previously treated leg. Tactile reactivity was then assessed over a period of 3 hr (Postinjection). (A–C) Tactile reactivity after shock treatment. (D–F) Tactile reactivity 24 hr after shock treatment. (G–I) Tactile reactivity after capsaicin treatment, averaged over the 3 hr test period. In each set of panels, data are presented for the Treated Leg (left), Untreated Leg (center), and average across legs (Means, right). Asterisks indicate statistically significant differences (p < .05), and error bars depict ± SEM. The inset depicts the experimental design.

Figure 7

Exposure to fixed spaced stimulation reverses capsaicin-induced EMR. Rats received baseline assessments of tactile reactivity prior to subcutaneous hindpaw injections of 1% capsaicin or saline (50 μL) into the dorsal surface of one hindpaw. Tactile reactivity was assessed over the next 3 hr (Postinjection). Subjects then received 1,800 fixed spaced shocks, or nothing (Unshk), to the previously injected (Treated) leg. Tactile reactivity was then re-assessed (Postshock). (A–C) Tactile reactivity after capsaicin treatment, averaged over the 3 hr of testing. (D–F) Tactile reactivity after shock treatment in rats that had previously received saline (open bars) or capsaicin (filled bars). In each set of panels, data are presented for the Treated Leg (left), Untreated Leg (center), and average across legs (Means, right). Asterisks indicate statistically significant differences (p < .05), and error bars depict ± SEM. The inset depicts the experimental design.