General Anesthesia Blocks Pain-Induced Hemorrhage and Locomotor Deficits After Spinal Cord Injury in Rats.

Research has shown that engaging pain (nociceptive) pathways after spinal cord injury (SCI) aggravates secondary injury and undermines locomotor recovery. This is significant because SCI is commonly accompanied by additional tissue damage (polytrauma) that drives nociceptive activity. Cutting communication with the brain by means of a surgical transection, or pharmacologically transecting the cord by slowly infusing a sodium channel blocker (lidocaine) rostral to a thoracic contusion, blocks pain-induced hemorrhage. These observations suggest that the adverse effect of pain after SCI depends on supraspinal (brain) systems. We hypothesize that inhibiting brain activity using a general anesthetic (e.g., pentobarbital, isoflurane) should have a protective effect. The present study shows that placing rats in an anesthetic state with pentobarbital or isoflurane 24 h after a lower thoracic contusion injury blocks pain-induced intraspinal inflammation and hemorrhage when administered before pain. Pentobarbital also extends protective effects against locomotor deficits produced by noxious stimulation. Inducing anesthesia after noxious stimulation, however, has no effect. Similarly, subanesthetic dosages of pentobarbital were also ineffective at blocking pain-induced hemorrhage. Also examined were the hemodynamic impacts of both pain and anesthetic delivery after SCI. Peripheral pain-input induced an acute increase in systolic blood pressure; isoflurane and pentobarbital prevent this increase, which may contribute to the protective effect of anesthesia. The results suggest that placing patients with SCI in a state akin to a medically induced coma can have a protective effect that blocks the adverse effects of pain.

Noxious Stimulation Induces Acute Hemorrhage and Impairs Long-Term Recovery after Spinal Cord Injury (SCI) in Female Rats: Evidence Estrous Cycle May Have a Modulatory Effect.

Spinal cord injuries (SCIs) are often the result of traumatic accidents, which also produce multiple other injuries (polytrauma). Nociceptive input from associated injuries has been shown to significantly impair recovery post-SCI. Historically, work in our laboratory has focused exclusively on male animals; however, increasing incidence of SCI in females requires research to determine whether pain (nociceptive) input poses the same risk to their recovery. Some animal studies have shown that females demonstrate greater tissue preservation and better locomotor recovery post-SCI. Given this, we examined the effect of sex on SCI recovery in two pain models-intermittent electrical stimulation (shock) to the tail or capsaicin injection to the hindpaw. Female rats received a lower thoracic contusion injury and were exposed to noxious stimulation the next day. The acute effect of noxious input on cardiovascular function, locomotor performance, and hemorrhage were assessed. Treatment with capsaicin or noxious electrical stimulation disrupted locomotor performance, increased blood pressure, and disrupted stepping. Additional experiments examined the long-term consequences of noxious input, demonstrating that both noxious electrical stimulation and capsaicin impair long-term recovery in female rats. Interestingly, injury had a greater effect on behavioral performance when progesterone and estrogen were low (metestrus). Conversely, nociceptive input led to a greater disruption in locomotor performance and produced a greater rise in blood pressure in animals injured during estrus.

Hemorrhage and Locomotor Deficits Induced by Pain Input after Spinal Cord Injury Are Partially Mediated by Changes in Hemodynamics.

Nociceptive input diminishes recovery and increases lesion area after a spinal cord injury (SCI). Recent work has linked these effects to the expansion of hemorrhage at the site of injury. The current article examines whether these adverse effects are linked to a pain-induced rise in blood pressure (BP) and/or flow. Male rats with a low-thoracic SCI were treated with noxious input (electrical stimulation [shock] or capsaicin) soon after injury. Locomotor recovery and BP were assessed throughout. Tissues were collected 3 h, 24 h, or 21 days later. Both electrical stimulation and capsaicin undermined locomotor function and increased the area of hemorrhage. Changes in BP/flow varied depending on type of noxious input, with only shock producing changes in BP. Providing behavioral control over the termination of noxious stimulation attenuated the rise in BP and hemorrhage. Pretreatment with the α-1 adrenergic receptor inverse agonist, prazosin, reduced the stimulation-induced rise in BP and hemorrhage. Prazosin also attenuated the adverse effect that noxious stimulation has on long-term recovery. Administration of the adrenergic agonist, norepinephrine 1 day after injury induced an increase in BP and disrupted locomotor function, but had little effect on hemorrhage. Further, inducing a rise in BP/flow using norepinephrine undermined long-term recovery and increased tissue loss. Mediational analyses suggest that the pain-induced rise in blood flow may foster hemorrhage after SCI. Increased BP appears to act through an independent process to adversely affect locomotor performance, tissue sparing, and long-term recovery.

Contribution of Brain Processes to Tissue Loss After Spinal Cord Injury: Does a Pain-Induced Rise in Blood Pressure Fuel Hemorrhage?

Pain (nociceptive) input soon after spinal cord injury (SCI) expands the area of tissue loss (secondary injury) and impairs long-term recovery. Evidence suggests that nociceptive stimulation has this effect because it promotes acute hemorrhage. Disrupting communication with the brain blocks this effect. The current study examined whether rostral systems exacerbate tissue loss because pain input drives an increase in systolic blood pressure (BP) and flow that fuels blood infiltration. Rats received a moderate contusion injury to the lower thoracic (T12) spinal cord. Communication with rostral processes was disrupted by cutting the spinal cord 18 h later at T2. Noxious electrical stimulation (shock) applied to the tail (Experiment 1), or application of the irritant capsaicin to one hind paw (Experiment 2), increased hemorrhage at the site of injury. Shock, but not capsaicin, increased systolic BP and tail blood flow in sham-operated rats. Cutting communication with the brain blocked the shock-induced increase in systolic BP and tail blood flow. Experiment 3 examined the effect of artificially driving a rise in BP with norepinephrine (NE) in animals that received shock. Spinal transection attenuated hemorrhage in vehicle-treated rats. Treatment with NE drove a robust increase in BP and tail blood flow but did not increase the extent of hemorrhage. The results suggest pain input after SCI can engage rostral processes that fuel hemorrhage and drive sustained cardiovascular output. An increase in BP was not, however, necessary or sufficient to drive hemorrhage, implicating other brain-dependent processes.

Pharmacological Transection of Brain-Spinal Cord Communication Blocks Pain-Induced Hemorrhage and Locomotor Deficits after Spinal Cord Injury in Rats.

Spinal cord injury (SCI) is often accompanied by additional tissue damage (polytrauma), which engages pain (nociceptive) fibers. Prior research has shown that nociceptive input can increase cell death, expand the area of hemorrhage, and impair long-term recovery. The current study shows that these adverse effects can be blocked by the sodium channel blocker lidocaine applied rostral to a contusion injury. Rats received a lower thoracic (T12) contusion injury, and noxious electrical stimulation (shock) was applied to the tail 24 h later. Immediately before shock treatment, a pharmacological transection was performed by slowly infusing lidocaine at T2. Long-term locomotor recovery was assessed over the next 21 days. Noxious electrical stimulation impaired locomotor recovery, and this effect was blocked by rostral lidocaine. Next, the acute effect of lidocaine was assessed. Tissue was collected 3 h after noxious stimulation, and the extent of hemorrhage was evaluated by assessing hemoglobin content using Western blotting. Nociceptive stimulation increased the extent of hemorrhage. Lidocaine applied at T2 before, but not immediately after, stimulation blocked this effect. A similar pattern of results was observed when lidocaine was applied at the site of injury by means of a lumbar puncture. The results show that a pharmacological transection blocks nociception-induced hemorrhage and exacerbation of locomotor deficits.

Learning to promote recovery after spinal cord injury.

The present review explores the concept of learning within the context of neurorehabilitation after spinal cord injury (SCI). The aim of physical therapy and neurorehabilitation is to bring about a lasting change in function-to encourage learning. Traditionally, it was assumed that the adult spinal cord is hardwired-immutable and incapable of learning. Research has shown that neurons within the lower (lumbosacral) spinal cord can support learning after communication with the brain has been disrupted by means of a thoracic transection. Noxious stimulation can sensitize nociceptive circuits within the spinal cord, engaging signal pathways analogous to those implicated in brain-dependent learning and memory. After a spinal contusion injury, pain input can fuel hemorrhage, increase the area of tissue loss (secondary injury), and undermine long-term recovery. Neurons within the spinal cord are sensitive to environmental relations. This learning has a metaplastic effect that counters neural over-excitation and promotes adaptive learning through an up-regulation of brain-derived neurotrophic factor (BDNF). Exposure to rhythmic stimulation, treadmill training, and cycling also enhances the expression of BDNF and counters the development of nociceptive sensitization. SCI appears to enable plastic potential within the spinal cord by down-regulating the Cl- co-transporter KCC2, which reduces GABAergic inhibition. This enables learning, but also fuels over-excitation and nociceptive sensitization. Pairing epidural stimulation with activation of motor pathways also promotes recovery after SCI. Stimulating motoneurons in response to activity within the motor cortex, or a targeted muscle, has a similar effect. It is suggested that a neurofunctionalist approach can foster the discovery of processes that impact spinal function and how they may be harnessed to foster recovery after SCI.

A brief period of moderate noxious stimulation induces hemorrhage and impairs locomotor recovery after spinal cord injury.

Spinal cord injury (SCI) is often accompanied by additional tissue damage (polytrauma) that provides a source of pain input. Our studies suggest that this pain input may be detrimental to long-term recovery. In a rodent model, we have shown that engaging pain (nociceptive) fibers caudal to a lower thoracic contusion SCI impairs recovery of locomotor function and increases tissue loss (secondary injury) and hemorrhage at the site of injury. In these studies, nociceptive fibers were activated using intermittent electrical stimulation. The stimulation parameters were derived from earlier studies demonstrating that 6 min of noxious stimulation, at an intensity (1.5 mA) that engages unmyelinated C (pain) fibers, induces a form of maladaptive plasticity within the lumbosacral spinal cord. We hypothesized that both shorter bouts of nociceptive input and lower intensities of stimulation will decrease locomotor function and increase spinal cord hemorrhage when rats have a spinal cord contusion. To test this, the present study exposed rats to electrical stimulation 24 h after a moderate lower thoracic contusion SCI. One group of rats received 1.5 mA stimulation for 0, 14.4, 72, or 180 s. Another group received six minutes of stimulation at 0, 0.17, 0.5, and 1.5 mA. Just 72 s of stimulation induced an acute disruption in motor performance, increased hemorrhage, and undermined the recovery of locomotor function. Likewise, less intense (0.5 mA) stimulation produced an acute disruption in motor performance, fueled hemorrhage, and impaired long-term recovery. The results imply that a brief period of moderate pain input can trigger hemorrhage after SCI and undermine long-term recovery. This highlights the importance of managing nociceptive signals after concurrent peripheral and central nervous system injuries.

Brain-Dependent Processes Fuel Pain-Induced Hemorrhage After Spinal Cord Injury.

Pain (nociceptive) input caudal to a spinal contusion injury can undermine long-term recovery and increase tissue loss (secondary injury). Prior work suggests that nociceptive stimulation has this effect because it fosters the breakdown of the blood-spinal cord barrier (BSCB) at the site of injury, allowing blood to infiltrate the tissue. The present study examined whether these effects impact tissue rostral and caudal to the site of injury. In addition, the study evaluated whether cutting communication with the brain, by means of a rostral transection, affects the development of hemorrhage. Eighteen hours after rats received a lower thoracic (T11-12) contusion injury, half underwent a spinal transection at T2. Noxious electrical stimulation (shock) was applied 6 h later. Cellular assays showed that, in non-transected rats, nociceptive stimulation increased hemoglobin content, activated pro-inflammatory cytokines and engaged signals related to cell death at the site of injury. These effects were not observed in transected animals. In the next experiment, the spinal transection was performed at the time of contusion injury. Nociceptive stimulation was applied 24 h later and tissue was sectioned for microscopy. In non-transected rats, nociceptive stimulation increased the area of hemorrhage and this effect was blocked by spinal transection. These findings imply that the adverse effect of noxious stimulation depends upon spared ascending fibers and the activation of rostral (brain) systems. If true, stimulation should induce less hemorrhage after a severe contusion injury that blocks transmission to the brain. To test this, rats were given a mild, moderate, or severe, injury and electrical stimulation was applied 24 h later. Histological analyses of longitudinal sections showed that nociceptive stimulation triggered less hemorrhage after a severe contusion injury. The results suggest that brain-dependent processes drive pain-induced hemorrhage after spinal cord injury (SCI).

Engaging pain fibers after a spinal cord injury fosters hemorrhage and expands the area of secondary injury.

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.

Pain Input After Spinal Cord Injury (SCI) Undermines Long-Term Recovery and Engages Signal Pathways That Promote Cell Death.

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.