Research has shown that spinal circuits have the capacity to adapt in response to training, nociceptive stimulation and peripheral inflammation. These changes in neural function are mediated by physiological and neurochemical systems analogous to those that support plasticity within the hippocampus (e.g., long-term potentiation and the NMDA receptor). As observed in the hippocampus, engaging spinal circuits can have a lasting impact on plastic potential, enabling or inhibiting the capacity to learn. These effects are related to the concept of metaplasticity. Behavioral paradigms are described that induce metaplastic effects within the spinal cord. Uncontrollable/unpredictable stimulation, and peripheral inflammation, induce a form of maladaptive plasticity that inhibits spinal learning. Conversely, exposure to controllable or predictable stimulation engages a form of adaptive plasticity that counters these maladaptive effects and enables learning. Adaptive plasticity is tied to an up-regulation of brain derived neurotrophic factor (BDNF). Maladaptive plasticity is linked to processes that involve kappa opioids, the metabotropic glutamate (mGlu) receptor, glia, and the cytokine tumor necrosis factor (TNF). Uncontrollable nociceptive stimulation also impairs recovery after a spinal contusion injury and fosters the development of pain (allodynia). These adverse effects are related to an up-regulation of TNF and a down-regulation of BDNF and its receptor (TrkB). In the absence of injury, brain systems quell the sensitization of spinal circuits through descending serotonergic fibers and the serotonin 1A (5HT 1A) receptor. This protective effect is blocked by surgical anesthesia. Disconnected from the brain, intracellular Cl- concentrations increase (due to a down-regulation of the cotransporter KCC2), which causes GABA to have an excitatory effect. It is suggested that BDNF has a restorative effect because it up-regulates KCC2 and re-establishes GABA-mediated inhibition.

Research has shown that sensory feedback modulates locomotor behavior in intact as well as spinal adult animals. Here we examined if locomotor activity (“stepping”) in newborn rats is influenced by cutaneous and proprioceptive feedback. One-day-old rats were treated with the serotonergic receptor agonist quipazine (3.0 mg/kg) to induce air-stepping behavior or with saline (vehicle control). During stepping, a substrate/floor (elastic, stiff, or none) was placed beneath their limbs so that the feet could make plantar surface contact with a substrate. Pups treated with quipazine showed significantly more alternated fore- and hindlimb steps and plantar paw contact with the substrate, compared to pups treated with saline. Pups also made proportionately less contact with the stiff substrate versus the elastic substrate during stepping. Different types of movements made on the substrate (paw pushes, taps, swipes, and stances) were also characterized. These results indicate that sensory feedback modulates locomotor mechanisms and behavior in perinatal rats.

In humans, spinal cord injury (SCI) is often accompanied by additional tissue damage (polytrauma) that can engage pain (nociceptive) fibers. Prior work has shown that this nociceptive input can expand the area of tissue damage (secondary injury), undermine behavioral recovery, and enhance the development of chronic pain. Here, it is shown that nociceptive input given a day after a lower thoracic contusion injury in rats enhances the infiltration of red blood cells at the site of injury, producing an area of hemorrhage that expands secondary injury. Peripheral nociceptive fibers were engaged 24 h after injury by means of electrical stimulation (shock) applied at an intensity that engages unmyelinated pain (C) fibers or through the application of the irritant capsaicin. Convergent western immunoblot and cyanmethemoglobin colorimetric assays showed that both forms of stimulation increased the concentration of hemoglobin at the site of injury, with a robust effect observed 3–24 h after stimulation. Histopathology confirmed that shock treatment increased the area of hemorrhage and the infiltration of red blood cells. SCI can lead to hemorrhage by engaging the sulfonylurea receptor 1 (SUR1) transient receptor potential melastatin 4 (TRPM4) channel complex in neurovascular endothelial cells, which leads to cell death and capillary fragmentation. Histopathology confirmed that areas of hemorrhage showed capillary fragmentation. Co-immunoprecipitation of the SUR1-TRPM4 complex showed that it was up-regulated by noxious stimulation. Shock-induced hemorrhage was associated with an acute disruption in locomotor performance. These results imply that noxious stimulation impairs long-term recovery because it amplifies the breakdown of the blood spinal cord barrier (BSCB) and the infiltration of red blood cells, which expands the area of secondary injury.

More than 90% of spinal cord injuries are caused by traumatic accidents and are often associated with other tissue damage (polytrauma) that can provide a source of continued pain input during recovery. In a clinically relevant spinal cord contusion injury model, prior work has shown that noxious stimulation at an intensity that engages pain (C) fibers soon after injury augments secondary injury and impairs functional recovery. Noxious input increases the expression of pro-inflammatory cytokines (interleukin 1β and 18), cellular signals associated with cell death (caspase 3 and 8), and physiological signs of hemorrhage. Here, it is shown that reducing neural excitability after spinal cord injury (SCI) with the local anesthetic lidocaine (micro-injected by means of a lumbar puncture) blocks these adverse cellular effects. In contrast, treatment with an analgesic dose of morphine had no effect. Contused rats that received nociceptive stimulation soon after injury exhibited poor locomotor recovery, less weight gain, and greater tissue loss at the site of injury. Prophylactic application of lidocaine blocked the adverse effect of nociceptive stimulation on behavioral recovery and reduced tissue loss from secondary injury. The results suggest that quieting neural excitability using lidocaine can reduce the adverse effect of pain input (from polytrauma or surgery) after SCI.

Pain (nociceptive) input caudal to a spinal contusion injury increases tissue loss and impairs long-term recovery. It was hypothesized that noxious stimulation has this effect because it engages unmyelinated pain (C) fibers that produce a state of over-excitation in central pathways. The present article explored this issue by assessing the effect of capsaicin, which activates C-fibers that express the transient receptor potential vanilloid receptor-1 (TRPV1). Rats received a lower thoracic (T11) contusion injury and capsaicin was applied to one hind paw the next day. For comparison, other animals received noxious electrical stimulation at an intensity that engages C fibers. Both forms of stimulation elicited similar levels of c-fos mRNA expression, a cellular marker of nociceptive activation, and impaired long-term behavioral recovery. Cellular assays were then performed to compare the acute effect of shock and capsaicin treatment. Both forms of noxious stimulation increased expression of tumor necrosis factor (TNF) and caspase-3, which promotes apoptotic cell death. Shock, but not capsaicin, enhanced expression of signals related to pyroptotic cell death [caspase-1, inteleukin-1 beta (IL-1ß)]. Pyroptosis has been linked to the activation of the P2X7 receptor and the outward flow of adenosine triphosphate (ATP) through the pannexin-1 channel. Blocking the P2X7 receptor with Brilliant Blue G (BBG) reduced the expression of signals related to pyroptotic cell death in contused rats that had received shock. Blocking the pannexin-1 channel with probenecid paradoxically had the opposite effect. BBG enhanced long-term recovery and lowered reactivity to mechanical stimulation applied to the girdle region (an index of chronic pain), but did not block the adverse effect of nociceptive stimulation. The results suggest that C-fiber input after injury impairs long-term recovery and that this effect may arise because it induces apoptotic cell death.