Prior studies have shown that neurons within the spinal cord are sensitive to response-outcome relations, a form of instrumental learning. Spinally transected rats that receive shock to one hind leg learn to maintain the leg in a flexed position that minimizes net shock exposure (controllable shock). Prior exposure to uncontrollable stimulation (intermittent shock) inhibits this spinally mediated learning. Here it is shown that uncontrollable stimulation undermines the recovery of function after a spinal contusion injury. Rats received a moderate injury (12.5 mm drop) and recovery was monitored for 6 weeks. In Experiment 1, rats received varying amounts of intermittent tailshock 1-2 days after injury. Just 6 min of intermittent shock impaired locomotor recovery. In Experiment 2, rats were shocked 1, 4, or 14 days after injury. Delaying the application of shock exposure reduced its negative effect on recovery. In Experiment 3, rats received controllable or uncontrollable shock 24 and 48 h after injury. Only uncontrollable shock disrupted recovery of locomotor function. Uncontrollably shocked rats also exhibited higher vocalization thresholds to aversive stimuli (heat and shock) applied below the injury. Across the three experiments, exposure to uncontrollable shock, (1) delayed the recovery of bladder function; (2) led to greater mortality and spasticity; and (3) increased tissue loss (white and gray matter) in the region of the injury. The results indicate that uncontrollable stimulation impairs recovery after spinal cord injury and suggest that reducing sources of uncontrolled afferent input (e.g., from peripheral tissue injury) could benefit patient recovery.

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The Basso, Beattie, Bresnahan (BBB) open field locomotor scale is a popular measure of functional recovery following spinal cord injury (SCI). To examine the metric properties of the scale, we performed detailed analyses of BBB scores from 643 rats with moderate and severe SCI (12.5, 25, or 50 mm MASCIS) from two different laboratories. The analyses revealed that the BBB scale is ordinal in the most frequently used portion of the scale. Higher scores (14 and greater) were not frequently assigned in the dataset as animals with mild injuries were not sampled, making the ordinal nature of the upper end of the scale difficult to assess. The rare scores assigned in this range disproportionately increased variance. Under these conditions collapsing scores above 14 into one category increased effect size. Analysis of the lower region of the scale revealed that some scores (2 and 3) were rarely assigned, implying a discontinuity in the scale. The discontinuous nature of the lower portion of the scale presents a problem for both parametric and nonparametric statistical analyses. Pooling scores 2/3/4 eliminated the gap, enhancing the metric properties of the scale. Under the injury conditions evaluated, the transformation helped assure that the data were continuous and ordered. Further, interval durations were comparable across the entire range of the transformed scale, allowing application of parametric statistical techniques. The transformation should be applied in a post hoc fashion to reduce variability and increase power in cases where few scores fall in upper portion of the scale.

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Extrasynaptic α5‐subunit containing GABAA (α5‐GABAA) receptors participate in chronic pain. Previously, we reported a sex difference in the action of α5‐GABAA receptors in dysfunctional pain. However, the underlying mechanisms remain unknown. The aim of this study was to examine this sexual dimorphism in neuropathic rodents and the mechanisms involved. Female and male Wistar rats or ICR mice were subjected to nerve injury followed by α5‐GABAA receptor inverse agonist intrathecal administration, L‐655,708. The drug produced an antiallodynic effect in nerve‐injured female rats and mice, and a lower effect in males. We hypothesized that changes in α5‐GABAA receptor, probably influenced by hormonal and epigenetic status, might underlie this sex difference. Thus, we performed qPCR and western blot. Nerve injury increased α5‐GABAA mRNA and protein in female dorsal root ganglia (DRG) and decreased them in DRG and spinal cord of males. To investigate the hormonal influence over α5‐GABAA receptor actions, we performed nerve injury to ovariectomized rats and reconstituted them with 17β‐estradiol (E2). Ovariectomy abrogated L‐655,708 antiallodynic effect and E2 restored it. Ovariectomy decreased α5‐GABAA receptor and estrogen receptor α protein in DRG of neuropathic female rats, while E2 enhanced them. Since DNA methylation might contribute to α5‐GABAA receptor down‐regulation in males, we examined CpG island DNA methylation of α5‐GABAA receptor coding gene through pyrosequencing. Nerve injury increased methylation in male, but not female rats. Pharmacological inhibition of DNA methyltransferases increased α5‐GABAA receptor and enabled L‐655,708 antinociceptive effect in male rats. These results suggest that α5‐GABAA receptor is a suitable target to treat chronic pain in females.

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