Clinical trials.gov (NCT00615342).

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.

Using spinally transected rats, research has shown that neurons within the L4-S2 spinal cord are sensitive to response-outcome (instrumental) relations. This learning depends on a form of N-methyl-D-aspartate (NMDA)-mediated plasticity. Instrumental training enables subsequent learning, and this effect has been linked to the expression of brain-derived neurotrophic factor. Rats given uncontrollable stimulation later exhibit impaired instrumental learning, and this deficit lasts up to 48 hr. The induction of the deficit can be blocked by prior training with controllable shock, the concurrent presentation of a tonic stimulus that induces antinociception, or pretreatment with an NMDA or gamma-aminobutyric acid-A antagonist. The expression of the deficit depends on a kappa opioid. Uncontrollable stimulation enhances mechanical reactivity (allodynia), and treatments that induce allodynia (e.g., inflammation) inhibit learning. In intact animals, descending serotonergic neurons exert a protective effect that blocks the adverse consequences of uncontrollable stimulation. Uncontrollable, but not controllable, stimulation impairs the recovery of function after a contusion injury.

Nociceptive stimulation, at an intensity that elicits pain-related behavior, attenuates recovery of locomotor and bladder functions, and increases tissue loss after a contusion injury. These data imply that nociceptive input (e.g., from tissue damage) can enhance the loss of function after injury, and that potential clinical treatments, such pretreatment with an analgesic, may protect the damaged system from further secondary injury. The current study examined this hypothesis and showed that a potential treatment (morphine) did not have a protective effect. In fact, morphine appeared to exacerbate the effects of nociceptive stimulation. Experiment 1 showed that after spinal cord injury 20 mg/kg of systemic morphine was necessary to induce strong antinociception and block behavioral reactivity to shock treatment, a dose that was much higher than that needed for sham controls. In Experiment 2, contused rats were given one of three doses of morphine (Vehicle, 10, 20 mg/kg) prior to exposure to uncontrollable electrical stimulation or restraint alone. Despite decreasing nociceptive reactivity, morphine did not attenuate the long-term consequences of shock. Rats treated with morphine and shock had higher mortality rates, and displayed allodynic responses to innocuous sensory stimuli three weeks later. Independent of shock, morphine per se undermined recovery of sensory function. Rats treated with morphine alone also had significantly larger lesions than those treated with saline. These results suggest that nociceptive stimulation affects recovery despite a blockade of pain-elicited behavior. The results are clinically important because they suggest that opiate treatment may adversely affect the recovery of function after injury.

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