Publications by authors named "Michelle Hook"

42 Publications

Inflammation increases the development of depression behaviors in male rats after spinal cord injury.

Brain Behav Immun Health 2021 Jul 19;14:100258. Epub 2021 Apr 19.

Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M University, Medical Research and Education Building, Ste. 1005 8447 Riverside Pkwy, Bryan, TX, 77807, United States.

Following spinal cord injury, 18-26% of patients are diagnosed with depressive disorders, compared to 8-12% in the general population. As increased inflammation strongly correlates with depression in both animal and human studies, we hypothesized that the immune activation inherent to SCI could increase depression-like behavior. Thus, we proposed that reducing immune activation with minocycline, a microglial inhibitor, would decrease depression-like behavior following injury. Male Sprague-Dawley rats were given minocycline in their drinking water for 14 days following a moderate, mid-thoracic (T12) spinal contusion. An array of depression-like behaviors (social activity, sucrose preference, forced swim, open field activity) were examined prior to injury as well as on days 9-10, 19-20, and 29-30 post-injury. Peripheral cytokine levels were analyzed in serum collected prior to injury and 10 days post-injury. Hierarchical cluster analysis divided subjects into two groups based on behavior: depressed and not-depressed. Depressed subjects displayed lower levels of open field activity and social interaction relative to their not-depressed counterparts. Depressed subjects also showed significantly greater expression of pro-inflammatory cytokines both before and after injury and displayed lower levels of hippocampal neurogenesis than not-depressed subjects. Intriguingly, subjects who later showed depressive behaviors had higher baseline levels of the pro-inflammatory cytokine IL-6, which persisted throughout the duration of the experiment. Minocycline, however, did not affect serum cytokine levels and did not block the development of depression; equal numbers of minocycline versus vehicle-treated subjects appeared in both phenotypic groups. Despite this, these data overall suggest that molecular correlates of inflammation prior to injury could predict the development of depression after a physical stressor.
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http://dx.doi.org/10.1016/j.bbih.2021.100258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8474513PMC
July 2021

Fully Implantable Plantar Cutaneous Augmentation System for Rats Using Closed-loop Electrical Nerve Stimulation.

IEEE Trans Biomed Circuits Syst 2021 04 25;15(2):326-338. Epub 2021 May 25.

Plantar cutaneous feedback plays an important role in stable and efficient gait, by modulating the activity of ankle dorsi- and plantar-flexor muscles. However, central and peripheral nervous system trauma often decrease plantar cutaneous feedback and/or interneuronal excitability in processing the plantar cutaneous feedback. In this study, we tested a fully implantable neural recording and stimulation system augmenting plantar cutaneous feedback. Electromyograms were recorded from the medial gastrocnemius muscle for stance phase detection, while biphasic stimulation pulses were applied to the distal-tibial nerve during the stance phase to augment plantar cutaneous feedback. A Bluetooth low energy and a Qi-standard inductive link were adopted for wireless communication and wireless charging, respectively. To test the operation of the system, one intact rat walked on a treadmill with the electrical system implanted into its back. Leg kinematics were recorded to identify the stance phase. Stimulation was applied, with a 250-ms onset delay from stance onset and 200-ms duration, resulting in the onset at 47.58 ± 2.82% of stance phase and the offset at 83.49 ± 4.26% of stance phase (Mean ± SEM). The conduction velocity of the compound action potential (31.2 m/s and 41.6 m/s at 1·T and 2·T, respectively) suggests that the evoked action potential was characteristic of an afferent volley for cutaneous feedback. We also demonstrated successful wireless charging and system reset functions. The experimental results suggest that the presented implantable system can be a valuable neural interface tool to investigate the effect of plantar cutaneous augmentation on gait in a rat model.
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http://dx.doi.org/10.1109/TBCAS.2021.3072894DOI Listing
April 2021

Closed-Loop Plantar Cutaneous Augmentation by Electrical Nerve Stimulation Increases Ankle Plantarflexion During Treadmill Walking.

IEEE Trans Biomed Eng 2021 09 19;68(9):2798-2809. Epub 2021 Aug 19.

Ankle plantarflexion plays an important role in forward propulsion and anterior-posterior balance during locomotion. This component of gait is often critically impacted by neurotraumas and neurological diseases. We hypothesized that augmenting plantar cutaneous feedback, via closed-loop distal-tibial nerve stimulation, could increase ankle plantarflexion during walking. To test the hypothesis, one intact rat walked on a motorized treadmill with implanted electronic device and electrodes for closed-loop neural recording and stimulation. Constant-current biphasic electrical pulse train was applied to distal-tibial nerve, based on electromyogram recorded from the medial gastrocnemius muscle, to be timed with the stance phase. The stimulation current threshold to evoke plantar cutaneous feedback was set at 30 μA (1·T), based on compound action potential evoked by stimulation. The maximum ankle joint angle at plantarflexion, during the application of stimulation currents of 3.3·T and 6.6·T, respectively, was increased from 149.4° (baseline) to 165.4° and 161.6°. The minimum ankle joint angle at dorsiflexion was decreased from 59.4° (baseline) to 53.1°, during the application of stimulation currents of 3.3·T, but not changed by 6.6·T. Plantar cutaneous augmentation also changed other gait kinematic parameters. Stance duty factor was increased from 51.9% (baseline) to 65.7% and 64.0%, respectively, by 3.3·T and 6.6·T, primarily due to a decrease in swing duration. Cycle duration was consistently decreased by the stimulation. In the control trial after two stimulation trials, a strong after-effect was detected in overall gait kinematics as well as ankle plantarflexion, suggesting that this stimulation has the potential for producing long-term changes in gait kinematics.
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http://dx.doi.org/10.1109/TBME.2021.3054564DOI Listing
September 2021

Cytisine is neuroprotective in female but not male 6-hydroxydopamine lesioned parkinsonian mice and acts in combination with 17-β-estradiol to inhibit apoptotic endoplasmic reticulum stress in dopaminergic neurons.

J Neurochem 2021 05 10;157(3):710-726. Epub 2021 Jan 10.

Department of Neuroscience & Experimental Therapeutics, College of Medicine, Texas A&M University, Bryan, TX, USA.

Apoptotic endoplasmic reticulum (ER) stress is a major mechanism for dopaminergic (DA) loss in Parkinson's disease (PD). We assessed if low doses of the partial α4β2 nicotinic acetylcholine receptor agonist, cytisine attenuates apoptotic ER stress and exerts neuroprotection in substantia nigra pars compacta (SNc) DA neurons. Alternate day intraperitoneal injections of 0.2 mg/kg cytisine were administered to female and male mice with 6-hydroxydopamine (6-OHDA) lesions in the dorsolateral striatum, which caused unilateral degeneration of SNc DA neurons. Cytisine attenuated 6-OHDA-induced PD-related behaviors in female, but not in male mice. We also found significant reductions in tyrosine hydroxylase (TH) loss within the lesioned SNc of female, but not male mice. In contrast to female mice, DA neurons within the lesioned SNc of male mice showed a cytisine-induced pathological increase in the nuclear translocation of the pro-apoptotic ER stress protein, C/EBP homologous protein (CHOP). To assess the role of estrogen in cytisine neuroprotection in female mice, we exposed primary mouse DA cultures to either 10 nM 17-β-estradiol and 200 nM cytisine or 10 nM 17-β-estradiol alone. 17-β-estradiol reduced expression of CHOP, whereas cytisine exposure reduced 6-OHDA-mediated nuclear translocation of two other ER stress proteins, activating transcription factor 6 and x-box-binding protein 1, but not CHOP. Taken together, these data show that cytisine and 17-β-estradiol work in combination to inhibit all three arms (activating transcription factor 6, x-box-binding protein 1, and CHOP) of apoptotic ER stress signaling in DA neurons, which can explain the neuroprotective effect of low-dose cytisine in female mice.
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http://dx.doi.org/10.1111/jnc.15282DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8106636PMC
May 2021

Variability in Open-Field Locomotor Scoring Following Force-Defined Spinal Cord Injury in Rats: Quantification and Implications.

Front Neurol 2020 9;11:650. Epub 2020 Jul 9.

Department of Veterinary Pathobiology, Texas A&M University, College Station, TX, United States.

Spinal cord injury research in experimental animals aims to define mechanisms of tissue damage and identify interventions that can be translated into effective clinical therapies. Highly reliable models of injury and outcome measurement are essential to achieve these aims and avoid problems with reproducibility. Functional scoring is a critical component of outcome assessment and is currently commonly focused on open field locomotion (the "BBB score"). Here we analyze variability of observed locomotor outcome after a highly regulated spinal cord contusion in a large group of rats that had not received any therapeutic intervention. Our data indicate that, despite tight regulation of the injury severity, there is considerable variability in open-field score of individual rats at 21 days after injury, when the group as a whole reaches a functional plateau. The bootstrapped reference interval (that defines boundaries that contain 95% scores in the population without regard for data distributional character) for the score at 21 days was calculated to range from 2.3 to 15.9 on the 22-point scale. Further analysis indicated that the mean day 21 score of random groups of 10 individuals drawn by bootstrap sampling from the whole study population varies between 9.5 and 13.5. Wide variability between individuals implies that detection of small magnitude group-level treatment effects will likely be unreliable, especially if using small experimental group sizes. To minimize this problem in intervention studies, consideration should be given to assessing treatment effects by comparing proportions of animals in comparator groups that attain pre-specified criterion scores.
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http://dx.doi.org/10.3389/fneur.2020.00650DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7363775PMC
July 2020

The first 24 h: opioid administration in people with spinal cord injury and neurologic recovery.

Spinal Cord 2020 Oct 27;58(10):1080-1089. Epub 2020 May 27.

Department of Neuroscience and Experimental Therapeutics, Texas A&M Health Science Center, Bryan, TX, USA.

Study Design: Retrospective chart review.

Objectives: The objective of this study was to characterize opioid administration in people with acute SCI and examine the association between opioid dose and (1) changes in motor/functional scores from hospital to rehabilitation discharge, and (2) pain, depression, and quality of life (QOL) scores 1-year post injury.

Setting: Spinal Cord Injury Model System (SCIMS) inpatient acute rehabilitation facility.

Methods: Patients included in the SCIMS from 2008 to 2011 were linked to the National Trauma Registry and the electronic medical record. Three opioid dose groups (low, medium, and high) were defined based on the total morphine equivalence in milligrams at 24 h. The associations between opioid dose groups and functional/motor outcomes were assessed, as well as 1-year follow-up pain and QOL surveys.

Results: In all, 85/180 patients had complete medication records. By 24 h, all patients had received opioids. Patients receiving higher amounts of opioids had higher pain scores 1 year later compared with medium- and low-dose groups (pain levels 5.5 vs. 4 vs. 1, respectively, p = 0.018). There was also an 8× greater risk of depression 1 year later in the high-dose group compared with the low-dose group (OR: 8.1, 95% CI: 1.2-53.7). In analyses of motor scores, we did not find a significant interaction between opioid dose and duration of injury.

Conclusions: These preliminary findings suggest that higher doses of opioids administered within 24 h of injury are associated with increased pain in the chronic phase of people with SCI.
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http://dx.doi.org/10.1038/s41393-020-0483-xDOI Listing
October 2020

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

Physiol Behav 2019 12 21;212:112695. Epub 2019 Oct 21.

Cellular and Behavioral Neuroscience, Department of Psychology, Texas A&M University, College Station, TX 77843, USA.

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.
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http://dx.doi.org/10.1016/j.physbeh.2019.112695DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7326330PMC
December 2019

SCI and depression: Does inflammation commandeer the brain?

Exp Neurol 2019 10 13;320:112977. Epub 2019 Jun 13.

School of Medicine, Department of Neuroscience and Experimental Therapeutics, Texas A&M University, Medical Research and Education Building, Ste. 1005, 8447 Riverside Pkwy, Bryan, TX 77807, United States; Texas A&M Institute of Neuroscience, Texas A&M University, Interdisciplinary Life Sciences Building, Rm 3148, 3474 College Station, TAMU, TX, United States.

The incidence of depression is almost twice as high in the spinally injured population compared to the general population. While this incidence has long been attributed to the psychological, economic, and social burdens that accompany spinal cord injury (SCI), data from animal studies indicate that the biology of SCI may play an important role in the development of depression. Inflammation has been shown to impact stress response in rodents and humans, and inflammatory cytokines have been associated with depression for decades. The inflammation inherent to SCI may disrupt necessary mechanisms of mental homeostasis, such as serotonin production, dopamine production, and the hypothalamic pituitary adrenal axis. Additionally, gut dysbiosis that occurs after SCI can exacerbate inflammation and may cause further mood and behavior changes. These mediators combined may significantly contribute to the rise in depression seen after SCI. Currently, there are no therapies specific to depression after SCI. Elucidation of the molecular pathways that contribute to SCI-specific depression is crucial for the understanding of this disease and its potential treatments.
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http://dx.doi.org/10.1016/j.expneurol.2019.112977DOI Listing
October 2019

Depression-like behavior corresponds with cardiac changes in a rodent model of spinal cord injury.

Exp Neurol 2019 10 31;320:112969. Epub 2019 May 31.

School of Medicine, Department of Neuroscience and Experimental Therapeutics, Medical Research and Education Building, Texas A&M University, Ste. 1005, 8447 Riverside Pkwy, Bryan, TX 77807, United States; Texas A&M Institute of Neuroscience, Interdisciplinary Life Sciences Building, Texas A&M University, Rm 3148, 3474 TAMU, College Station, TX, United States.

In previous studies we have shown that approximately 1/3 of male Sprague Dawley rats develop symptoms of depression following a spinal cord injury (SCI). Using established behavioral tests to measure depression in rodents, we found that after SCI, subjects characterized as depressed had decreased sucrose preference, open field activity, social exploration, and burrowing behavior. As some of these tests of depression could be affected by the compromised motor function inherent to the SCI condition, the current study examined whether non-subjective, physiological differences in heart rate and heart rate variability were also associated with depression, as seen in humans. Male Sprague Dawley rats were implanted with radiotelemetry devices and either received a moderate contusion injury or remained intact. The implanted telemetry devices recorded home cage activity, body temperature, heart rate, and heart rate variability for 5 min/h throughout a 30-day post-injury assessment period. Depression behavior was evaluated using a battery of tests conducted on days 9-10 and 19-20 post-injury. Locomotor recovery and pain reactivity were also examined. Hierarchical clustering, based on the behavioral scores collected on the tests of depression, revealed that 28% of the SCI subjects displayed symptoms of depression, relative to the remaining 72% of SCI subjects. The subjects characterized as depressed had significantly lower social interaction and burrowing activity than the group that was not depressed. Interestingly, the subjects behaviorally characterized as depressed also had significantly lower heart rate variability than the not-depressed intact group. There was no difference between not-depressed SCI and intact rats on this measure. Therefore, in addition to behavior, depressed and not-depressed rats differ on measures of physiological function that are associated with depression in humans. These physiological differences further validate the rodent model of depression after SCI.
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http://dx.doi.org/10.1016/j.expneurol.2019.112969DOI Listing
October 2019

Morphine increases macrophages at the lesion site following spinal cord injury: Protective effects of minocycline.

Brain Behav Immun 2019 07 23;79:125-138. Epub 2019 Jan 23.

Department of Neuroscience and Experimental Therapeutics, Texas A&M Health Science Center, United States. Electronic address:

Opioids are among the most effective and widely prescribed medications for the treatment of pain following spinal cord injury (SCI). Spinally-injured patients receive opioids within hours of arrival at the emergency room, and prolonged opioid regimens are often employed for the management of post-SCI chronic pain. However, previous studies in our laboratory suggest that the effects of opioids such as morphine may be altered in the pathophysiological context of neurotrauma. Specifically, we have shown that morphine administration in a rodent model of SCI increases mortality and tissue loss at the injury site, and decreases recovery of motor and sensory function, and overall health, even weeks after treatment. The literature suggests that opioids may produce these adverse effects by acting as endotoxins and increasing glial activation and inflammation. To better understand the effects of morphine following SCI, in this study we used flow cytometry to assess immune-competent cells at the lesion site. We observed a morphine-induced increase in the overall number of CD11b+ cells, with marked effects on microglia, in SCI subjects. Next, to investigate whether this increase in the inflammatory profile is necessary to produce morphine's effects, we challenged morphine treatment with minocycline. We found that pre-treatment with minocycline reduced the morphine-induced increase in microglia at the lesion site. More importantly, minocycline also blocked the adverse effects of morphine on recovery of function without disrupting the analgesic efficacy of this opioid. Together, our findings suggest that following SCI, morphine may exacerbate the inflammatory response, increasing cell death at the lesion site and negatively affecting functional recovery.
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http://dx.doi.org/10.1016/j.bbi.2019.01.023DOI Listing
July 2019

Osteocytes reflect a pro-inflammatory state following spinal cord injury in a rodent model.

Bone 2019 03 11;120:465-475. Epub 2018 Dec 11.

Department of Neuroscience and Experimental Therapeutics, Texas A&M Health Science Center, Bryan, TX, United States of America. Electronic address:

Profound bone loss occurs following spinal cord injury (SCI) resulting in a high incidence of fractures. While likely caused in part by loss of weight-bearing, there is greater bone loss following SCI when compared to that observed in other disuse animal models. Patients with SCI have a protracted inflammatory response, with elevated circulating levels of pro-inflammatory markers. This chronic inflammation could compound the bone loss attributed to disuse and the loss of neural signaling. To assess this, we examined inflammatory markers and bone turnover regulators in osteocytes from rats with a moderate spinal contusion injury (SCI) and intact controls (CON). We counted osteocytes positive for cytokines [tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-17 (IL-17), and interleukin-10 (IL-10)], osteoclastogenesis regulators RANKL and OPG, and the bone formation inhibitor sclerostin, 32 days after the spinal contusion. By day 9 post-injury, the majority of SCI rats had recovered significant locomotor function and were bearing weight on their hindlimbs. However, despite weight-bearing, peripheral QCT scans demonstrated lower bone mass due to SCI in the proximal tibia metaphysis compared to CON. SCI animals also had lower cancellous bone volume, lower bone formation rate (BFR), lower osteoid surface (OS), and higher osteoclast surface (Oc.S). Tibial mid-shaft periosteal BFR was also lower after SCI. Immunohistochemical staining of the distal femur bone revealed cancellous osteocytes positive for TNF-α, IL-6, IL-17, and IL-10 were elevated in SCI animals relative to intact controls. Protein expression of RANKL+, OPG+, and sclerostin+ osteocytes was also higher in SCI rats. At the cortical midshaft, osteocyte TNF-α, IL-6, and sclerostin were statistically higher in SCI vs. CON. With regression analysis, inflammatory factors were associated with changes in bone turnover. In conclusion, inflammatory factors as well as altered mechanical loading influence bone turnover following a moderate SCI. Treatments aimed at minimizing fracture risk after SCI may need to target both the chronically altered inflammatory state as well as disuse-induced bone loss.
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http://dx.doi.org/10.1016/j.bone.2018.12.007DOI Listing
March 2019

Pain Input Impairs Recovery after Spinal Cord Injury: Treatment with Lidocaine.

J Neurotrauma 2017 03 2;34(6):1200-1208. Epub 2016 Dec 2.

1 Behavioral and Cellular Neuroscience, Department of Psychology, Texas A&M University , College Station, Texas.

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.
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http://dx.doi.org/10.1089/neu.2016.4778DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5359686PMC
March 2017

Neurobiological Effects of Morphine after Spinal Cord Injury.

J Neurotrauma 2017 02 2;34(3):632-644. Epub 2016 Nov 2.

4 Department of Physiology, Emory University School of Medicine , Atlanta, Georgia .

Opioids and non-steroidal anti-inflammatory drugs are used commonly to manage pain in the early phase of spinal cord injury (SCI). Despite its analgesic efficacy, however, our studies suggest that intrathecal morphine undermines locomotor recovery and increases lesion size in a rodent model of SCI. Similarly, intravenous (IV) morphine attenuates locomotor recovery. The current study explores whether IV morphine also increases lesion size after a spinal contusion (T12) injury and quantifies the cell types that are affected by early opioid administration. Using an experimenter-administered escalating dose of IV morphine across the first seven days post-injury, we quantified the expression of neuron, astrocyte, and microglial markers at the injury site. SCI decreased NeuN expression relative to shams. In subjects with SCI treated with IV morphine, virtually no NeuN cells remained across the rostral-caudal extent of the lesion. Further, whereas SCI per se increased the expression of astrocyte and microglial markers (glial fibrillary acidic protein and OX-42, respectively), morphine treatment decreased the expression of these markers. These cellular changes were accompanied by attenuation of locomotor recovery (Basso, Beattie, Bresnahan scores), decreased weight gain, and the development of opioid-induced hyperalgesia (increased tactile reactivity) in morphine-treated subjects. These data suggest that morphine use is contraindicated in the acute phase of a spinal injury. Faced with a lifetime of intractable pain, however, simply removing any effective analgesic for the management of SCI pain is not an ideal option. Instead, these data underscore the critical need for further understanding of the molecular pathways engaged by conventional medications within the pathophysiological context of an injury.
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http://dx.doi.org/10.1089/neu.2016.4507DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5286553PMC
February 2017

When Pain Hurts: Nociceptive Stimulation Induces a State of Maladaptive Plasticity and Impairs Recovery after Spinal Cord Injury.

J Neurotrauma 2017 05 20;34(10):1873-1890. Epub 2016 Dec 20.

2 Department of Neuroscience and Experimental Therapeutics, Texas A&M Health Science Center , Bryan, Texas.

Spinal cord injury (SCI) is often accompanied by other tissue damage (polytrauma) that provides a source of pain (nociceptive) input. Recent findings are reviewed that show SCI places the caudal tissue in a vulnerable state that exaggerates the effects nociceptive stimuli and promotes the development of nociceptive sensitization. Stimulation that is both unpredictable and uncontrollable induces a form of maladaptive plasticity that enhances nociceptive sensitization and impairs spinally mediated learning. In contrast, relational learning induces a form of adaptive plasticity that counters these adverse effects. SCI sets the stage for nociceptive sensitization by disrupting serotonergic (5HT) fibers that quell overexcitation. The loss of 5HT can enhance neural excitability by reducing membrane-bound K-Cl cotransporter 2, a cotransporter that regulates the outward flow of Cl. This increases the intracellular concentration of Cl, which reduces the hyperpolarizing (inhibitory) effect of gamma-aminobutyric acid. Uncontrollable noxious stimulation also undermines the recovery of locomotor function, and increases behavioral signs of chronic pain, after a contusion injury. Nociceptive stimulation has a greater effect if experienced soon after SCI. This adverse effect has been linked to a downregulation in brain-derived neurotrophic factor and an upregulation in the cytokine, tumor necrosis factor. Noxious input enhances tissue loss at the site of injury by increasing the extent of hemorrhage and apoptotic/pyroptotic cell death. Intrathecal lidocaine blocks nociception-induced hemorrhage, cellular indices of cell death, and its adverse effect on behavioral recovery. Clinical implications are discussed.
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http://dx.doi.org/10.1089/neu.2016.4626DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5444485PMC
May 2017

Nor-Binaltorphimine Blocks the Adverse Effects of Morphine after Spinal Cord Injury.

J Neurotrauma 2017 03 4;34(6):1164-1174. Epub 2016 Nov 4.

Department of Neuroscience and Experimental Therapeutics, Texas A&M Health Science Center , Bryan, Texas.

Opioids are frequently used for the treatment of pain following spinal cord injury (SCI). Unfortunately, we have shown that morphine administered in the acute phase of SCI results in significant, adverse secondary consequences including compromised locomotor and sensory recovery. Similarly, we showed that selective activation of the κ-opioid receptor (KOR), even at a dose 32-fold lower than morphine, is sufficient to attenuate recovery of locomotor function. In the current study, we tested whether activation of the KOR is necessary to produce morphine's adverse effects using nor-Binaltorphimine (norBNI), a selective KOR antagonist. Rats received a moderate spinal contusion (T12) and 24 h later, baseline locomotor function and nociceptive reactivity were assessed. Rats were then administered norBNI (0, 0.02, 0.08, or 0.32 μmol) followed by morphine (0 or 0.32 μmol). Nociception was reassessed 30 min after drug treatment, and recovery was evaluated for 21 days. The effects of norBNI on morphine-induced attenuation of recovery were dose dependent. At higher doses, norBNI blocked the adverse effects of morphine on locomotor recovery, but analgesia was also significantly decreased. Conversely, at low doses, analgesia was maintained, but the adverse effects on recovery persisted. A moderate dose of norBNI, however, adequately protected against morphine's adverse effects without eliminating its analgesic efficacy. This suggests that activation of the KOR system plays a significant role in the morphine-induced attenuation of recovery. Our research suggests that morphine, and other opioid analgesics, may be contraindicated for the SCI population. Blocking KOR activity may be a viable strategy for improving the safety of clinical opioid use.
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http://dx.doi.org/10.1089/neu.2016.4601DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5359644PMC
March 2017

Inflammation is increased with anxiety- and depression-like signs in a rat model of spinal cord injury.

Brain Behav Immun 2016 Jan 18;51:176-195. Epub 2015 Aug 18.

Department of Neuroscience and Experimental Therapeutics, Texas A&M Health Science Center, Bryan, TX, USA.

Spinal cord injury (SCI) leads to increased anxiety and depression in as many as 60% of patients. Yet, despite extensive clinical research focused on understanding the variables influencing psychological well-being following SCI, risk factors that decrease it remain unclear. We hypothesized that excitation of the immune system, inherent to SCI, may contribute to the decrease in psychological well-being. To test this hypothesis, we used a battery of established behavioral tests to assess depression and anxiety in spinally contused rats. The behavioral tests, and subsequent statistical analyses, revealed three cohorts of subjects that displayed behavioral characteristics of (1) depression, (2) depression and anxiety, or (3) no signs of decreased psychological well-being. Subsequent molecular analyses demonstrated that the psychological cohorts differed not only in behavioral symptoms, but also in peripheral (serum) and central (hippocampi and spinal cord) levels of pro-inflammatory cytokines. Subjects exhibiting a purely depression-like profile showed higher levels of pro-inflammatory cytokines peripherally, whereas subjects exhibiting a depression- and anxiety-like profile showed higher levels of pro-inflammatory cytokines centrally (hippocampi and spinal cord). These changes in inflammation were not associated with injury severity; suggesting that the association between inflammation and the expression of behaviors characteristic of decreased psychological well-being was not confounded by differential impairments in motor ability. These data support the hypothesis that inflammatory changes are associated with decreased psychological well-being following SCI.
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http://dx.doi.org/10.1016/j.bbi.2015.08.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4679693PMC
January 2016

Regulatory effects of intermittent noxious stimulation on spinal cord injury-sensitive microRNAs and their presumptive targets following spinal cord contusion.

Front Neural Circuits 2014 18;8:117. Epub 2014 Sep 18.

Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M Health Science Center Bryan, TX, USA.

Uncontrollable nociceptive stimulation adversely affects recovery in spinally contused rats. Spinal cord injury (SCI) results in altered microRNA (miRNA) expression both at, and distal to the lesion site. We hypothesized that uncontrollable nociception further influences SCI-sensitive miRNAs and associated gene targets, potentially explaining the progression of maladaptive plasticity. Our data validated previously described sensitivity of miRNAs to SCI alone. Moreover, following SCI, intermittent noxious stimulation decreased expression of miR124 in dorsal spinal cord 24 h after stimulation and increased expression of miR129-2 in dorsal, and miR1 in ventral spinal cord at 7 days. We also found that brain-derived neurotrophic factor (BDNF) mRNA expression was significantly down-regulated 1 day after SCI alone, and significantly more so, after SCI followed by tailshock. Insulin-like growth factor-1 (IGF-1) mRNA expression was significantly increased at both 1 and 7 days post-SCI, and significantly more so, 7 days post-SCI with shock. MiR1 expression was positively and significantly correlated with IGF-1, but not BDNF mRNA expression. Further, stepwise linear regression analysis indicated that a significant proportion of the changes in BDNF and IGF-1 mRNA expression were explained by variance in two groups of miRNAs, implying co-regulation. Collectively, these data show that uncontrollable nociception which activates sensorimotor circuits distal to the injury site, influences SCI-miRNAs and target mRNAs within the lesion site. SCI-sensitive miRNAs may well mediate adverse consequences of uncontrolled sensorimotor activation on functional recovery. However, their sensitivity to distal sensory input also implicates these miRNAs as candidate targets for the management of SCI and neuropathic pain.
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http://dx.doi.org/10.3389/fncir.2014.00117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4166958PMC
May 2015

Metaplasticity and behavior: how training and inflammation affect plastic potential within the spinal cord and recovery after injury.

Front Neural Circuits 2014 8;8:100. Epub 2014 Sep 8.

Department of Physiology, Emory University School of Medicine Atlanta, GA, USA.

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.
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http://dx.doi.org/10.3389/fncir.2014.00100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4157609PMC
May 2015

Peripheral noxious stimulation reduces withdrawal threshold to mechanical stimuli after spinal cord injury: role of tumor necrosis factor alpha and apoptosis.

Pain 2014 Nov 29;155(11):2344-59. Epub 2014 Aug 29.

Department of Psychology, Texas A&M University, College Station, TX 77843, USA.

We previously showed that peripheral noxious input after spinal cord injury (SCI) inhibits beneficial spinal plasticity and impairs recovery of locomotor and bladder functions. These observations suggest that noxious input may similarly affect the development and maintenance of chronic neuropathic pain, an important consequence of SCI. In adult rats with a moderate contusion SCI, we investigated the effect of noxious tail stimulation, administered 1 day after SCI on mechanical withdrawal responses to von Frey stimuli from 1 to 28 days after treatment. In addition, because the proinflammatory cytokine tumor necrosis factor alpha (TNFα) is implicated in numerous injury-induced processes including pain hypersensitivity, we assessed the temporal and spatial expression of TNFα, TNF receptors, and several downstream signaling targets after stimulation. Our results showed that unlike sham surgery or SCI only, nociceptive stimulation after SCI induced mechanical sensitivity by 24h. These behavioral changes were accompanied by increased expression of TNFα. Cellular assessments of downstream targets of TNFα revealed that nociceptive stimulation increased the expression of caspase 8 and the active subunit (12 kDa) of caspase 3, indicative of active apoptosis at a time point consistent with the onset of mechanical allodynia. In addition, immunohistochemical analysis revealed distinct morphological signs of apoptosis in neurons and microglia at 24h after stimulation. Interestingly, expression of the inflammatory mediator NFκB was unaltered by nociceptive stimulation. These results suggest that noxious input caudal to the level of SCI can increase the onset and expression of behavioral responses indicative of pain, potentially involving TNFα signaling.
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http://dx.doi.org/10.1016/j.pain.2014.08.034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4253555PMC
November 2014

The association between spinal cord trauma-sensitive miRNAs and pain sensitivity, and their regulation by morphine.

Neurochem Int 2014 Nov 24;77:40-9. Epub 2014 May 24.

Department of Neuroscience & Experimental Therapeutics, College of Medicine, Texas A&M Health Science Center, Bryan, TX 77807-3260, USA. Electronic address:

Increased pain sensitivity is a common sequela to spinal cord injury (SCI). Moreover, drugs like morphine, though critical for pain management, elicit pro-inflammatory effects that exacerbate chronic pain symptoms. Previous reports showed that SCI results in the induction and suppression of several microRNAs (miRNAs), both at the site of injury, as well as in segments of the spinal cord distal to the injury site. We hypothesized that morphine would modulate the expression of these miRNAs, and that expression of these SCI-sensitive miRNAs may predict adaptation of distal nociceptive circuitry following SCI. To determine whether morphine treatment further dysregulates SCI-sensitive miRNAs, their expression was examined by qRT-PCR in sham controls and in response to vehicle and morphine treatment following contusion in rats, at either 2 or 15 days post-SCI. Our data indicated that expression of miR1, miR124, and miR129-2 at the injury site predicted the nociceptive response mediated by spinal regions distal to the lesion site, suggesting a molecular mechanism for the interaction of SCI with adaptation of functionally intact distal sensorimotor circuitry. Moreover, the SCI-induced miRNA, miR21 was induced by subsequent morphine administration, representing an alternate, and hitherto unidentified, maladaptive response to morphine exposure. Contrary to predictions, mRNA for the pro-inflammatory interleukin-6 receptor (IL6R), an identified target of SCI-sensitive miRNAs, was also induced following SCI, indicating dissociation between miRNA and target gene expression. Moreover, IL6R mRNA expression was inversely correlated with locomotor function suggesting that inflammation is a predictor of decreased spinal cord function. Collectively, our data indicate that miR21 and other SCI-sensitive miRNAs may constitute therapeutic targets, not only for improving functional recovery following SCI, but also for attenuating the effects of SCI on pain sensitivity.
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http://dx.doi.org/10.1016/j.neuint.2014.05.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4177361PMC
November 2014

Morphine self-administration following spinal cord injury.

J Neurotrauma 2014 Sep 24;31(18):1570-83. Epub 2014 Jul 24.

1 Texas A&M University Institute for Neuroscience , Texas A&M Health Science Center, Bryan, Texas.

Neuropathic pain develops in up to two-thirds of people following spinal cord injury (SCI). Opioids are among the most effective treatments for this pain and are commonly prescribed. There is concern surrounding the use of these analgesics, however, because use is often associated with the development of addiction. Previous data suggests that this concern may not be relevant in the presence of neuropathic pain. Yet, despite the common prescription of opioids for the treatment of SCI-related pain, there has been only one previous study examining the addictive potential of morphine following spinal injury. To address this, the present study used a self-administration paradigm to examine the addictive potential of morphine in a rodent model of SCI. Animals were placed into self-administration chambers 24 h, 14 d, or 35 d following a moderate spinal contusion injury. They were placed into the chambers for seven 12-hour sessions with access to 1.5 mg morphine/lever depression (up to 30 mg/d). In the acute phase of SCI, contused animals self-administered significantly less morphine than their sham counterparts, as previously shown. However, contused animals showing signs of neuropathic pain did not self-administer less morphine than their sham counterparts when administration began 14 or 35 d after injury. Instead, these animals administered nearly the full amount of morphine available each session. This amount of morphine did not affect recovery of locomotor function but did cause significant weight loss. We suggest caution is warranted when prescribing opioids for the treatment of neuropathic pain resulting from SCI, as the addictive potential is not reduced in this model.
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http://dx.doi.org/10.1089/neu.2013.3293DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4161170PMC
September 2014

Psychological stress as a modulator of functional recovery following spinal cord injury.

Front Neurol 2014 9;5:44. Epub 2014 Apr 9.

Department of Neuroscience and Experimental Therapeutics, Texas A&M Health Science Center, Texas A&M Institute for Neuroscience, College of Medicine , College Station, TX , USA.

There is strong evidence indicating that the social environment triggers changes to the psychological stress response and glucocorticoid receptor function. Considerable literature links the subsequent changes in stress resiliency to physical health. Here, converging evidence for the modulatory role of chronic psychological stress in the recovery process following spinal cord injury (SCI) is presented. Despite the considerable advances in SCI research, we are still unable to identify the causes of variability in patients' recovery following injury. We propose that individuals' past and present life experiences (in the form of stress exposure) may significantly modulate patients' outcome post-SCI. We propose a theoretical model to explain the negative impact of chronic psychological stress on physical and psychological recovery. The stress experienced in life prior to SCI and also as a result of the traumatic injury, could compromise glucocorticoid receptor sensitivity and function, and contribute to high levels of inflammation and apoptosis post-SCI, decreasing the tissue remaining at the injury site and undermining recovery of function. Both stress-induced glucocorticoid resistance and stress-induced epigenetic changes to the glucocorticoid receptor can modulate the nuclear factor-kappa B regulated inflammatory pathways and the Bcl-2 regulated apoptosis pathways. This model not only contributes to the theoretical understanding of the recovery process following injury, but also provides concrete testable hypotheses for future studies.
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http://dx.doi.org/10.3389/fneur.2014.00044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3988397PMC
June 2014

Assessment of depression in a rodent model of spinal cord injury.

J Neurotrauma 2014 Jun 8;31(12):1107-21. Epub 2014 May 8.

Department of Neuroscience and Experimental Therapeutics, Texas A&M Health Science Center , Bryan, Texas.

Despite an increased incidence of depression in patients after spinal cord injury (SCI), there is no animal model of depression after SCI. To address this, we used a battery of established tests to assess depression after a rodent contusion injury. Subjects were acclimated to the tasks, and baseline scores were collected before SCI. Testing was conducted on days 9-10 (acute) and 19-20 (chronic) postinjury. To categorize depression, subjects' scores on each behavioral measure were averaged across the acute and chronic stages of injury and subjected to a principal component analysis. This analysis revealed a two-component structure, which explained 72.2% of between-subjects variance. The data were then analyzed with a hierarchical cluster analysis, identifying two clusters that differed significantly on the sucrose preference, open field, social exploration, and burrowing tasks. One cluster (9 of 26 subjects) displayed characteristics of depression. Using these data, a discriminant function analysis was conducted to derive an equation that could classify subjects as "depressed" on days 9-10. The discriminant function was used in a second experiment examining whether the depression-like symptoms could be reversed with the antidepressant, fluoxetine. Fluoxetine significantly decreased immobility in the forced swim test (FST) in depressed subjects identified with the equation. Subjects that were depressed and treated with saline displayed significantly increased immobility on the FST, relative to not depressed, saline-treated controls. These initial experiments validate our tests of depression, generating a powerful model system for further understanding the relationships between molecular changes induced by SCI and the development of depression.
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http://dx.doi.org/10.1089/neu.2013.3204DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4062114PMC
June 2014

Opioid administration following spinal cord injury: implications for pain and locomotor recovery.

Exp Neurol 2013 Sep 15;247:328-41. Epub 2013 Mar 15.

Texas A&M Institute for Neuroscience, Department of Psychology, Texas A&M University, College Station, TX 77843-4235, USA.

Approximately one-third of people with a spinal cord injury (SCI) will experience persistent neuropathic pain following injury. This pain negatively affects quality of life and is difficult to treat. Opioids are among the most effective drug treatments, and are commonly prescribed, but experimental evidence suggests that opioid treatment in the acute phase of injury can attenuate recovery of locomotor function. In fact, spinal cord injury and opioid administration share several common features (e.g. central sensitization, excitotoxicity, aberrant glial activation) that have been linked to impaired recovery of function, as well as the development of pain. Despite these effects, the interactions between opioid use and spinal cord injury have not been fully explored. A review of the literature, described here, suggests that caution is warranted when administering opioids after SCI. Opioid administration may synergistically contribute to the pathology of SCI to increase the development of pain, decrease locomotor recovery, and leave individuals at risk for infection. Considering these negative implications, it is important that guidelines are established for the use of opioids following spinal cord and other central nervous system injuries.
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http://dx.doi.org/10.1016/j.expneurol.2013.03.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3742731PMC
September 2013

Maladaptive spinal plasticity opposes spinal learning and recovery in spinal cord injury.

Front Physiol 2012 10;3:399. Epub 2012 Oct 10.

Department of Neurological Surgery, Brain and Spinal Injury Center, University of California San Francisco San Francisco, CA, USA.

Synaptic plasticity within the spinal cord has great potential to facilitate recovery of function after spinal cord injury (SCI). Spinal plasticity can be induced in an activity-dependent manner even without input from the brain after complete SCI. A mechanistic basis for these effects is provided by research demonstrating that spinal synapses have many of the same plasticity mechanisms that are known to underlie learning and memory in the brain. In addition, the lumbar spinal cord can sustain several forms of learning and memory, including limb-position training. However, not all spinal plasticity promotes recovery of function. Central sensitization of nociceptive (pain) pathways in the spinal cord may emerge in response to various noxious inputs, demonstrating that plasticity within the spinal cord may contribute to maladaptive pain states. In this review we discuss interactions between adaptive and maladaptive forms of activity-dependent plasticity in the spinal cord below the level of SCI. The literature demonstrates that activity-dependent plasticity within the spinal cord must be carefully tuned to promote adaptive spinal training. Prior work from our group has shown that stimulation that is delivered in a limb position-dependent manner or on a fixed interval can induce adaptive plasticity that promotes future spinal cord learning and reduces nociceptive hyper-reactivity. On the other hand, stimulation that is delivered in an unsynchronized fashion, such as randomized electrical stimulation or peripheral skin injuries, can generate maladaptive spinal plasticity that undermines future spinal cord learning, reduces recovery of locomotor function, and promotes nociceptive hyper-reactivity after SCI. We review these basic phenomena, how these findings relate to the broader spinal plasticity literature, discuss the cellular and molecular mechanisms, and finally discuss implications of these and other findings for improved rehabilitative therapies after SCI.
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http://dx.doi.org/10.3389/fphys.2012.00399DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3468083PMC
October 2012

Impact of behavioral control on the processing of nociceptive stimulation.

Front Physiol 2012 10;3:262. Epub 2012 Aug 10.

Cellular and Behavioral Neuroscience, Department of Psychology, Texas A&M University College Station, TX, USA.

How nociceptive signals are processed within the spinal cord, and whether these signals lead to behavioral signs of neuropathic pain, depends upon their relation to other events and behavior. Our work shows that these relations can have a lasting effect on spinal plasticity, inducing a form of learning that alters the effect of subsequent nociceptive stimuli. The capacity of lower spinal systems to adapt, in the absence of brain input, is examined in spinally transected rats that receive a nociceptive shock to the tibialis anterior muscle of one hind leg. If shock is delivered whenever the leg is extended (controllable stimulation), it induces an increase in flexion duration that minimizes net shock exposure. This learning is not observed in subjects that receive the same amount of shock independent of leg position (uncontrollable stimulation). These two forms of stimulation have a lasting, and divergent, effect on subsequent learning: controllable stimulation enables learning whereas uncontrollable stimulation disables it (learning deficit). Uncontrollable stimulation also enhances mechanical reactivity. We review evidence that training with controllable stimulation engages a brain-derived neurotrophic factor (BDNF)-dependent process that can both prevent and reverse the consequences of uncontrollable shock. We relate these effects to changes in BDNF protein and TrkB signaling. Controllable stimulation is also shown to counter the effects of peripheral inflammation (from intradermal capsaicin). A model is proposed that assumes nociceptive input is gated at an early sensory stage. This gate is sensitive to current environmental relations (between proprioceptive and nociceptive input), allowing stimulation to be classified as controllable or uncontrollable. We further propose that the status of this gate is affected by past experience and that a history of uncontrollable stimulation will promote the development of neuropathic pain.
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http://dx.doi.org/10.3389/fphys.2012.00262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3429038PMC
October 2012

Analgesia or addiction?: implications for morphine use after spinal cord injury.

J Neurotrauma 2012 May 2;29(8):1650-62. Epub 2012 Apr 2.

Department of Psychology, Texas A&M University, College Station, TX 77843-4235, USA.

Opioid analgesics are among the most effective agents for treatment of moderate to severe pain. However, the use of morphine after a spinal cord injury (SCI) can potentiate the development of paradoxical pain symptoms, and continuous administration can lead to dependence, tolerance, and addiction. Although some studies suggest that the addictive potential of morphine decreases when it is used to treat neuropathic pain, this has not been studied in a SCI model. Accordingly, the present studies investigated the addictive potential of morphine in a rodent model of SCI using conditioned place preference (CPP) and intravenous self-administration paradigms. A contusion injury significantly increased the expression of a CPP relative to sham and intact controls in the acute phase of injury. However, contused animals self-administered significantly less morphine than sham and intact controls, but this was dose-dependent; at a high concentration, injured rats exhibited an increase in drug-reinforced responses over time. Exposure to a high concentration of morphine impeded weight gain and locomotor recovery. We suggest that the increased preference observed in injured rats reflects a motivational effect linked in part to the drug's anti-nociceptive effect. Further, although injured rats exhibited a suppression of opiate self-administration, when given access to a high concentration, addictive-like behavior emerged and was associated with poor recovery.
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http://dx.doi.org/10.1089/neu.2011.2100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3353755PMC
May 2012

An IL-1 receptor antagonist blocks a morphine-induced attenuation of locomotor recovery after spinal cord injury.

Brain Behav Immun 2011 Feb 23;25(2):349-59. Epub 2010 Oct 23.

Department of Psychology, Texas A&M University, College Station, TX 77843-4235, USA.

Morphine is one of the most commonly prescribed medications for the treatment of chronic pain after a spinal cord injury (SCI). Despite widespread use, however, little is known about the secondary consequences of morphine use after SCI. Unfortunately, our previous studies show that administration of a single dose of morphine, in the acute phase of a moderate spinal contusion injury, significantly attenuates locomotor function, reduces weight gain, and produces symptoms of paradoxical pain (Hook et al., 2009). The current study focused on the cellular mechanisms that mediate these effects. Based on data from other models, we hypothesized that pro-inflammatory cytokines might play a role in the morphine-induced attenuation of function. Experiment 1 confirmed that systemic morphine (20 mg/kg) administered one day after a contusion injury significantly increased expression levels of spinal IL-1β 24 h later. Experiment 2 extended these findings, demonstrating that a single dose of morphine (90 μg, i.t.) applied directly onto the spinal cord increased expression levels of spinal IL-1β at both 30 min and 24 h after administration. Experiment 3 showed that administration of an interleukin-1 receptor antagonist (IL-1ra, i.t.) prior to intrathecal morphine (90 μg), blocked the adverse effects of morphine on locomotor recovery. Further, pre-treatment with 3 μg IL-1ra prevented the increased expression of at-level neuropathic pain symptoms that was observed 28 days later in the group treated with morphine-alone. However, the IL-1ra also had adverse effects that were independent of morphine. Treatment with the IL-1ra alone undermined recovery of locomotor function, potentiated weight loss and significantly increased tissue loss at the injury site. Overall, these data suggest that morphine disrupts a critical balance in concentrations of pro-inflammatory cytokines in the spinal cord, and this undermines recovery of function.
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http://dx.doi.org/10.1016/j.bbi.2010.10.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3025088PMC
February 2011

Intrathecal morphine attenuates recovery of function after a spinal cord injury.

J Neurotrauma 2009 May;26(5):741-52

Department of Psychology, Texas A&M University, College Station, Texas 77843-4235, USA.

Prior work has shown that a high dose (20 mg/kg) of systemic morphine, required to produce significant analgesia in the acute phase of a contusion injury, undermines the long-term health of treated subjects and increases lesion size. Moreover, a single dose of systemic morphine in the early stage of injury (24 h post-injury) led to symptoms of neuropathic pain 3 weeks later, in the chronic phase. The present study examines the locus of the effects using intrathecal morphine administration. Subjects were treated with one of three doses (0, 30, or 90 microg) of intrathecal morphine 24 h after a moderate contusion injury. The 90-microg dose produced significant analgesia when subjects were exposed to noxious stimuli (thermal and incremented shock) below the level of injury. Yet, despite analgesic efficacy, intrathecal morphine significantly attenuated the recovery of locomotor function and increased lesion size rostral to the injury site. A single dose of 30 or 90 microg of intrathecal morphine also decreased weight gain, and more than doubled the incidence of mortality and autophagia when compared to vehicle-treated controls. Morphine is one of the most effective pharmacological agents for the treatment of neuropathic pain and, therefore, is indispensable for the spinally injured. Treatment can, however, adversely affect the recovery process. A morphine-induced attenuation of recovery may result from increases in immune cell activation and, subsequently, pro-inflammatory cytokine concentrations in the contused spinal cord.
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http://dx.doi.org/10.1089/neu.2008.0710DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2800819PMC
May 2009

Group I metabotropic glutamate receptors control metaplasticity of spinal cord learning through a protein kinase C-dependent mechanism.

J Neurosci 2008 Nov;28(46):11939-49

Brain and Spinal Injury Center, Department of Neurological Surgery, University of California, San Francisco, San Francisco, California 94110, USA.

Neurons within the spinal cord can support several forms of plasticity, including response-outcome (instrumental) learning. After a complete spinal transection, experimental subjects are capable of learning to hold the hindlimb in a flexed position (response) if shock (outcome) is delivered to the tibialis anterior muscle when the limb is extended. This response-contingent shock produces a robust learning that is mediated by ionotropic glutamate receptors (iGluRs). Exposure to nociceptive stimuli that are independent of limb position (e.g., uncontrollable shock; peripheral inflammation) produces a long-term (>24 h) inhibition of spinal learning. This inhibition of plasticity in spinal learning is itself a form of plasticity that requires iGluR activation and protein synthesis. Plasticity of plasticity (metaplasticity) in the CNS has been linked to group I metabotropic glutamate receptors (subtypes mGluR1 and mGluR5) and activation of protein kinase C (PKC). The present study explores the role of mGluRs and PKC in the metaplastic inhibition of spinal cord learning using a combination of behavioral, pharmacological, and biochemical techniques. Activation of group I mGluRs was found to be both necessary and sufficient for metaplastic inhibition of spinal learning. PKC was activated by stimuli that inhibit spinal learning, and inhibiting PKC activity restored the capacity for spinal learning. Finally, a PKC inhibitor blocked the metaplastic inhibition of spinal learning produced by a group I mGluR agonist. The data strongly suggest that group I mGluRs control metaplasticity of spinal learning through a PKC-dependent mechanism, providing a potential therapeutic target for promoting use-dependent plasticity after spinal cord injury.
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http://dx.doi.org/10.1523/JNEUROSCI.3098-08.2008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2628285PMC
November 2008
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