Eric Crown | Abbvie Bioresearch Center (original) (raw)

Papers by Eric Crown

Research paper thumbnail of Pain in a Balance: Noxious Events Engage Opposing Processes That Concurrently Modulate Nociceptive Reactivity

Behavioral Neuroscience, 2004

Studies have shown that noxious cutaneous stimulation engages physiologically different antinocic... more Studies have shown that noxious cutaneous stimulation engages physiologically different antinociceptive systems to inhibit a spinal reflex, tail withdrawal from radiant heat. Two experiments are reported that examine the relationship between the inhibition of the tail-flick response and brain-mediated responses to nociception. The induction of a spinally mediated antinociception was accompanied by an increase in latency to vocalize to a

Research paper thumbnail of Shock-induced hyperalgesia: III. Role of the bed nucleus of the stria terminalis and amygdaloid nuclei

Behavioral Neuroscience, 2000

Research paper thumbnail of Shock-Induced Hyperalgesia: IV. Generality

Journal of Experimental Psychology-animal Behavior Processes, 2001

Brief–moderate shock (3, 0.75 s, 1.0 mA) has opposite effects on different measures of pain, indu... more Brief–moderate shock (3, 0.75 s, 1.0 mA) has opposite effects on different measures of pain, inducing antinociception on the tail-flick test while lowering vocalization thresholds to shock and heat (hyperalgesia) and enhancing fear conditioned by a gridshock unconditioned stimulus (US). This study examined the generality of shock-induced hyperalgesia under a range of conditions and explored parallels to sensitized startle. Reduced

Research paper thumbnail of Instrumental learning within the spinal cord

Physiology & Behavior - PHYSIOL BEHAV, 2002

Rats spinally transected at the second thoracic vertebra can learn to maintain their leg in a fle... more Rats spinally transected at the second thoracic vertebra can learn to maintain their leg in a flexed position if they receive legshock for extending the limb. These rats display an increase in the duration of a flexion response that minimizes net shock exposure. The current set of experiments was designed to determine whether the acquisition of this behavioral response is mediated by the neurons of the spinal cord (i.e., is centrally mediated) or reflects a peripheral modification (e.g., a change in muscle tension). Experiment 1 found that preventing information from reaching the spinal cord by severing the sciatic nerve blocked the acquisition of this behavioral response. Spinalized rats also failed to learn if the spinal cord was anesthetized with lidocaine during exposure to response-contingent shock (Experiment 2). Experiment 3 demonstrated that prior exposure to response-contingent shock on one hindleg facilitated acquisition of the response when subjects were later tested on t...

Research paper thumbnail of Preserving and Restoring Behavioral Potential Within the Spinal Cord Using an Instrumental Training Paradigm

We have shown that spinal cord neurons can support a simple form of instrumental learning. In a t... more We have shown that spinal cord neurons can support a simple form of instrumental learning. In a typical experiment, rats are spinalized at the second thoracic vertebra (T(2)) and given shock to one hindleg. One group (master) receives shock whenever the leg is extended. This response-contingent shock causes an increase in response duration that decreases net shock exposure. This instrumental learning is not observed in yoked controls that receive the same amount of shock independent of leg position (noncontingent shock). Interestingly, rats that have received noncontingent shock also fail to learn when they are subsequently exposed to response-contingent shock on either the ipsilateral or contralateral leg. Just 6 min of noncontingent nociceptive stimulation, applied to the leg or tail, undermines behavioral potential for up to 48 h. The present experiments explore whether a behavioral therapy can prevent and/or reverse this deficit. In experiment 1, spinalized rats received 30 min of training with contingent shock, noncontingent shock, or nothing prior to noncontingent tailshock. They were then tested with contingent shock to the contralateral hindleg. Rats that had received noncontingent shock alone failed to learn. Prior exposure to contingent shock had an immunizing effect that prevented the deficit. Experiment 2 examined whether training with contingent shock after noncontingent shock exposure would restore behavioral potential. To facilitate performance during contingent shock training, subjects were given an intrathecal injection of the opioid antagonist naltrexone, a drug treatment that temporarily blocks the expression of the behavioral deficit. Twenty-four hours later subjects were tested with contingent shock on either the ipsilateral or contralateral leg. We found that naltrexone combined with contingent shock therapy restored spinal cord function. Naltrexone alone had no effect. The results suggest that noncontingent nociceptive stimulation can undermine behavioral potential after spinal cord injury and that instrumental training can help preserve, and protect, spinal cord function.

Research paper thumbnail of Changes in Motoneuron Properties and Synaptic Inputs Related to Step Training after Spinal Cord Transection in Rats

Journal of Neuroscience, 2007

Although recovery from spinal cord injury is generally meager, evidence suggests that step traini... more Although recovery from spinal cord injury is generally meager, evidence suggests that step training can improve stepping performance, particularly after neonatal spinal injury. The location and nature of the changes in neural substrates underlying the behavioral improvements are not well understood. We examined the kinematics of stepping performance and cellular and synaptic electrophysiological parameters in ankle extensor motoneurons in nontrained and treadmill-trained rats, all receiving a complete spinal transection as neonates. For comparison, electrophysiological experiments included animals injured as young adults, which are far less responsive to training.

Research paper thumbnail of Calcium/calmodulin dependent kinase II contributes to persistent central neuropathic pain following spinal cord injury

PAIN, 2012

Chronic central neuropathic pain after central nervous system injuries remains refractory to ther... more Chronic central neuropathic pain after central nervous system injuries remains refractory to therapeutic interventions. A novel approach would be to target key intracellular signaling proteins that are known to contribute to continued activation by phosphorylation of kinases, transcription factors, and/or receptors that contribute to changes in membrane excitability. We demonstrate that one signaling kinase, calcium/ calmodulin-dependent kinase II (CaMKII), is critical in maintaining aberrant dorsal horn neuron hyperexcitability in the neuropathic pain condition after spinal cord injury (SCI). After contusion SCI at spinal level T10, activated CaMKII (phosphorylated, pCaMKII) expression is significantly upregulated in the T7/8 spinal dorsal horn in neurons, but not glial cells, and in oligodendrocytes in the dorsal column in the same rats that displayed at-level mechanical allodynia. Furthermore, identified spinothalamic neurons demonstrated significant increases of pCaMKII after SCI compared to sham-treated control animals. However, neither astrocytes nor microglia showed pCaMKII expression in either sham-treated or SCI rats. To demonstrate causality, treatment of SCI rats with KN-93, which prevents CaMKII activation, significantly attenuated at-level mechanical allodynia and aberrant wide dynamic range neuronal activity evoked by brush, pressure, and pinch stimuli and a graded series of von Frey stimuli, respectively. Persistent CaMKII activation contributes to chronic central neuropathic pain by mechanisms that involve maintained hyperexcitability of wide dynamic range dorsal horn neurons. Furthermore, targeting key signaling proteins is a novel, useful therapeutic strategy for treating chronic central neuropathic pain.

Research paper thumbnail of HC-030031, a TRPA1 selective antagonist, attenuates inflammatory- and neuropathy-induced mechanical hypersensitivity

Molecular Pain, 2008

Background: Safe and effective treatment for chronic inflammatory and neuropathic pain remains a ... more Background: Safe and effective treatment for chronic inflammatory and neuropathic pain remains a key unmet medical need for many patients. The recent discovery and description of the transient receptor potential family of receptors including TRPV1 and TRPA1 has provided a number of potential new therapeutic targets for treating chronic pain. Recent reports have suggested that TRPA1 may play an important role in acute formalin and CFA induced pain. The current study was designed to further explore the therapeutic potential of pharmacological TRPA1 antagonism to treat inflammatory and neuropathic pain.

Research paper thumbnail of Uncontrollable Stimulation Undermines Recovery after Spinal Cord Injury

Journal of Neurotrauma, 2004

Prior studies have shown that neurons within the spinal cord are sensitive to response-outcome re... more Prior studies have shown that neurons within the spinal cord are sensitive to response-outcome relations, a form of instrumental learning. Spinally transected rats that receive shock to one hind leg learn to maintain the leg in a flexed position that minimizes net shock exposure (controllable shock). Prior exposure to uncontrollable stimulation (intermittent shock) inhibits this spinally mediated learning.

Research paper thumbnail of Instrumental learning within the spinal cord: underlying mechanisms and implications for recovery after injury

Behavioral and …, 2006

that how one answers this question has important implications for our views of learning, the regu... more that how one answers this question has important implications for our views of learning, the regulation of behavior, and the recovery of function after injury.

Research paper thumbnail of Instrumental learning within the spinal cord: V. Evidence the behavioral deficit observed after noncontingent nociceptive stimulation reflects an intraspinal modification

Behavioural Brain Research, 2003

Spinally transected rats given leg shock whenever one hindlimb is extended learn to maintain the ... more Spinally transected rats given leg shock whenever one hindlimb is extended learn to maintain the leg in a flexed position, which minimizes net shock exposure. Yoked rats, that receive an equal amount of shock independent of leg position (noncontingent shock), do not exhibit an increase in flexion duration. Yoked rats also fail to learn when response contingent shock is applied to the previously shocked leg, a behavioral deficit that resembles learned helplessness. This deficit could reflect either a peripheral (e.g. muscle fatigue) or central effect. Experiment 1 showed that spinalized rats given noncontingent shock to one hind limb fail to learn when response-contingent shock is applied to the contralateral leg. Experiment 2 demonstrated that blocking the afferent input to the spinal cord, by cutting the sciatic nerve, blocked the development of the deficit. Experiment 3 found that intrathecal lidocaine has a protective effect and prevents the deficit. These findings suggest that noncontingent nociceptive stimulation induces an intraspinal modification that undermines behavioral potential.

Research paper thumbnail of Two chronic motor training paradigms differentially influence acute instrumental learning in spinally transected rats

Behavioural Brain Research, 2007

The effect of two chronic motor training paradigms on the ability of the lumbar spinal cord to pe... more The effect of two chronic motor training paradigms on the ability of the lumbar spinal cord to perform an acute instrumental learning task was examined in neonatally (postnatal day 5; P5) spinal cord transected (i.e., spinal) rats. At ∼P30, rats began either unipedal hindlimb stand training (Stand-Tr; 20-25 min/day, 5 days/week), or bipedal hindlimb step training (Step-Tr; 20 min/day; 5 days/week) for 7 weeks. Non-trained spinal rats (Non-Tr) served as controls. After 7 weeks all groups were tested on the flexor-biased instrumental learning paradigm. We hypothesized that Step-Tr rats would exhibit an increased capacity to learn the flexor-biased task relative to Non-Tr subjects, as locomotion involves repetitive training of the tibialis anterior (TA), the ankle flexor whose activation is important for successful instrumental learning, and (2) Stand-Tr rats would exhibit a deficit in acute motor learning, as unipedal training activates the ipsilateral ankle extensors, but not flexors. Results showed no differences in acute learning potential between Non-Tr and Step-Tr rats, while the Stand-Tr group showed a reduced capacity to learn the acute task. Further investigation of the Stand-Tr group showed that, while both the ipsilateral and contralateral hindlimbs were significantly impaired in their acute learning potential, the contralateral, untrained hindlimbs exhibited significantly greater learning deficits. These results suggest that different types of chronic peripheral input may have a significant impact on the ability to learn a novel motor task, and demonstrate the potential for experience-dependent plasticity in the spinal cord in the absence of supraspinal connectivity.

Research paper thumbnail of Pain in a Balance: Noxious Events Engage Opposing Processes That Concurrently Modulate Nociceptive Reactivity

Behavioral Neuroscience, 2004

Studies have shown that noxious cutaneous stimulation engages physiologically different antinocic... more Studies have shown that noxious cutaneous stimulation engages physiologically different antinociceptive systems to inhibit a spinal reflex, tail withdrawal from radiant heat. Two experiments are reported that examine the relationship between the inhibition of the tail-flick response and brain-mediated responses to nociception. The induction of a spinally mediated antinociception was accompanied by an increase in latency to vocalize to a noxious thermal stimulus, suggesting pain inhibition. Physiological manipulations that eliminated the inhibition of the tail-flick reflex restored vocalization to thermal stimulation and revealed a concurrent sensitization that generally heightened behavioral reactivity. The results suggest that net pain is regulated by 2 opposing processes, a selective inhibition of nociceptive signals within the spinal cord and a general sensitization that heightens stimulus processing.

Research paper thumbnail of The Behavioral Deficit Observed Following Noncontingent Shock in Spinalized Rats Is Prevented by the Protein Synthesis Inhibitor Cycloheximide

Behavioral Neuroscience, 2004

Spinalized rats that receive shock when 1 hind limb is extended (contingent shock) exhibit an inc... more Spinalized rats that receive shock when 1 hind limb is extended (contingent shock) exhibit an increase in flexion duration, a simple form of instrumental learning. Rats that receive shock independent of leg position (noncontingent shock) do not exhibit an increase in flexion duration and fail to learn when tested with contingent shock 24 hr later. It appears that noncontingent shock induces an intraspinal modification that inhibits the capacity to learn. The authors propose that the mechanisms that underlie this effect depend on de novo protein synthesis. To evaluate this hypothesis, the authors gave spinalized rats the protein synthesis inhibitor cycloheximide (CXM) or saline intrathecally prior to, or immediately after, noncontingent shock exposure. Twenty-four hours later, rats were tested with contingent shock. Rats that received the vehicle and noncontingent shock failed to learn. CXM-treated shocked rats learned normally, suggesting that the learning deficit depends on protein synthesis within the spinal cord.

Research paper thumbnail of Instrumental Learning Within the Rat Spinal Cord: Localization of the Essential Neural Circuit

Behavioral Neuroscience, 2005

Following spinal transection of the upper thoracic spinal cord, male Sprague-Dawley rats given le... more Following spinal transection of the upper thoracic spinal cord, male Sprague-Dawley rats given legshock whenever a hindlimb is extended learn to maintain the leg in a flexed position. The region of the cord that mediates this instrumental learning was isolated using neuroanatomical tracing, localized infusion of lidocaine, and surgical transections. DiI and Fluoro-Gold microinjection at the site of shock application labeled motor neuron bodies of lamina IX in the lower lumbar region. Local application of the Na ϩϩ channel blocker lidocaine disrupted learning when it was applied over a region extending from the lower lumbar (L3) to upper sacral (S2) cord. The drug had no effect rostral or caudal to this region. Surgical transections as low as L4 had no effect on learning. Learning also survived a dual transection at L4 and S3, but not L4 and S2. The results suggest that the essential neural circuit lies between L4 and S3.

Research paper thumbnail of Instrumental learning within the spinal cord: IV. Induction and retention of the behavioral deficit observed after noncontingent shock

Behavioral Neuroscience, 2002

Research paper thumbnail of Shock-induced hyperalgesia: II. Role of the dorsolateral periaqueductal gray

Behavioral Neuroscience, 1999

Research paper thumbnail of Increases in the activated forms of ERK 1/2, p38 MAPK, and CREB are correlated with the expression of at-level mechanical allodynia following spinal cord injury

Experimental Neurology, 2006

Rats given moderate spinal cord injury (SCI) display increases in the expression of the activated... more Rats given moderate spinal cord injury (SCI) display increases in the expression of the activated form of the transcription factor cyclic AMP responsive element binding protein (CREB) in spinal segments of dermatomes corresponding to permanent mechanical allodynia, a model of chronic central neuropathic pain (CNP; (Crown, E.. Upregulation of the phosphorylated form of CREB in spinothalamic tract cells following spinal cord injury: relation to central neuropathic pain. Neurosci. Lett. 384, 139-144)). Given that not all rats that receive moderate SCI develop CNP, the current study was designed to further analyze changes in persistent CREB activation and in the activation state of upstream intracellular signaling cascades (e.g., mitogen-activated protein kinases [MAPKs]) in populations of rats that receive SCI and weeks later develop CNP and rats that receive SCI but do not develop CNP. The results indicate that activated kinases such as pERK 1/2, p-p38 MAPK, but not pJNK, are upregulated in injured rats that develop CNP as compared to injured rats that fail to develop CNP. In addition, the current results replicated our previous finding that activated CREB is upregulated following SCI, however, only in SCI rats that developed CNP. Taken together, these results indicate that activation of intracellular signaling cascades traditionally associated with long-term potentiation and memory is associated with the expression of chronic CNP following SCI.

Research paper thumbnail of Pain in a Balance: Noxious Events Engage Opposing Processes That Concurrently Modulate Nociceptive Reactivity

Behavioral Neuroscience, 2004

Studies have shown that noxious cutaneous stimulation engages physiologically different antinocic... more Studies have shown that noxious cutaneous stimulation engages physiologically different antinociceptive systems to inhibit a spinal reflex, tail withdrawal from radiant heat. Two experiments are reported that examine the relationship between the inhibition of the tail-flick response and brain-mediated responses to nociception. The induction of a spinally mediated antinociception was accompanied by an increase in latency to vocalize to a

Research paper thumbnail of Shock-induced hyperalgesia: III. Role of the bed nucleus of the stria terminalis and amygdaloid nuclei

Behavioral Neuroscience, 2000

Research paper thumbnail of Shock-Induced Hyperalgesia: IV. Generality

Journal of Experimental Psychology-animal Behavior Processes, 2001

Brief–moderate shock (3, 0.75 s, 1.0 mA) has opposite effects on different measures of pain, indu... more Brief–moderate shock (3, 0.75 s, 1.0 mA) has opposite effects on different measures of pain, inducing antinociception on the tail-flick test while lowering vocalization thresholds to shock and heat (hyperalgesia) and enhancing fear conditioned by a gridshock unconditioned stimulus (US). This study examined the generality of shock-induced hyperalgesia under a range of conditions and explored parallels to sensitized startle. Reduced

Research paper thumbnail of Instrumental learning within the spinal cord

Physiology & Behavior - PHYSIOL BEHAV, 2002

Rats spinally transected at the second thoracic vertebra can learn to maintain their leg in a fle... more Rats spinally transected at the second thoracic vertebra can learn to maintain their leg in a flexed position if they receive legshock for extending the limb. These rats display an increase in the duration of a flexion response that minimizes net shock exposure. The current set of experiments was designed to determine whether the acquisition of this behavioral response is mediated by the neurons of the spinal cord (i.e., is centrally mediated) or reflects a peripheral modification (e.g., a change in muscle tension). Experiment 1 found that preventing information from reaching the spinal cord by severing the sciatic nerve blocked the acquisition of this behavioral response. Spinalized rats also failed to learn if the spinal cord was anesthetized with lidocaine during exposure to response-contingent shock (Experiment 2). Experiment 3 demonstrated that prior exposure to response-contingent shock on one hindleg facilitated acquisition of the response when subjects were later tested on t...

Research paper thumbnail of Preserving and Restoring Behavioral Potential Within the Spinal Cord Using an Instrumental Training Paradigm

We have shown that spinal cord neurons can support a simple form of instrumental learning. In a t... more We have shown that spinal cord neurons can support a simple form of instrumental learning. In a typical experiment, rats are spinalized at the second thoracic vertebra (T(2)) and given shock to one hindleg. One group (master) receives shock whenever the leg is extended. This response-contingent shock causes an increase in response duration that decreases net shock exposure. This instrumental learning is not observed in yoked controls that receive the same amount of shock independent of leg position (noncontingent shock). Interestingly, rats that have received noncontingent shock also fail to learn when they are subsequently exposed to response-contingent shock on either the ipsilateral or contralateral leg. Just 6 min of noncontingent nociceptive stimulation, applied to the leg or tail, undermines behavioral potential for up to 48 h. The present experiments explore whether a behavioral therapy can prevent and/or reverse this deficit. In experiment 1, spinalized rats received 30 min of training with contingent shock, noncontingent shock, or nothing prior to noncontingent tailshock. They were then tested with contingent shock to the contralateral hindleg. Rats that had received noncontingent shock alone failed to learn. Prior exposure to contingent shock had an immunizing effect that prevented the deficit. Experiment 2 examined whether training with contingent shock after noncontingent shock exposure would restore behavioral potential. To facilitate performance during contingent shock training, subjects were given an intrathecal injection of the opioid antagonist naltrexone, a drug treatment that temporarily blocks the expression of the behavioral deficit. Twenty-four hours later subjects were tested with contingent shock on either the ipsilateral or contralateral leg. We found that naltrexone combined with contingent shock therapy restored spinal cord function. Naltrexone alone had no effect. The results suggest that noncontingent nociceptive stimulation can undermine behavioral potential after spinal cord injury and that instrumental training can help preserve, and protect, spinal cord function.

Research paper thumbnail of Changes in Motoneuron Properties and Synaptic Inputs Related to Step Training after Spinal Cord Transection in Rats

Journal of Neuroscience, 2007

Although recovery from spinal cord injury is generally meager, evidence suggests that step traini... more Although recovery from spinal cord injury is generally meager, evidence suggests that step training can improve stepping performance, particularly after neonatal spinal injury. The location and nature of the changes in neural substrates underlying the behavioral improvements are not well understood. We examined the kinematics of stepping performance and cellular and synaptic electrophysiological parameters in ankle extensor motoneurons in nontrained and treadmill-trained rats, all receiving a complete spinal transection as neonates. For comparison, electrophysiological experiments included animals injured as young adults, which are far less responsive to training.

Research paper thumbnail of Calcium/calmodulin dependent kinase II contributes to persistent central neuropathic pain following spinal cord injury

PAIN, 2012

Chronic central neuropathic pain after central nervous system injuries remains refractory to ther... more Chronic central neuropathic pain after central nervous system injuries remains refractory to therapeutic interventions. A novel approach would be to target key intracellular signaling proteins that are known to contribute to continued activation by phosphorylation of kinases, transcription factors, and/or receptors that contribute to changes in membrane excitability. We demonstrate that one signaling kinase, calcium/ calmodulin-dependent kinase II (CaMKII), is critical in maintaining aberrant dorsal horn neuron hyperexcitability in the neuropathic pain condition after spinal cord injury (SCI). After contusion SCI at spinal level T10, activated CaMKII (phosphorylated, pCaMKII) expression is significantly upregulated in the T7/8 spinal dorsal horn in neurons, but not glial cells, and in oligodendrocytes in the dorsal column in the same rats that displayed at-level mechanical allodynia. Furthermore, identified spinothalamic neurons demonstrated significant increases of pCaMKII after SCI compared to sham-treated control animals. However, neither astrocytes nor microglia showed pCaMKII expression in either sham-treated or SCI rats. To demonstrate causality, treatment of SCI rats with KN-93, which prevents CaMKII activation, significantly attenuated at-level mechanical allodynia and aberrant wide dynamic range neuronal activity evoked by brush, pressure, and pinch stimuli and a graded series of von Frey stimuli, respectively. Persistent CaMKII activation contributes to chronic central neuropathic pain by mechanisms that involve maintained hyperexcitability of wide dynamic range dorsal horn neurons. Furthermore, targeting key signaling proteins is a novel, useful therapeutic strategy for treating chronic central neuropathic pain.

Research paper thumbnail of HC-030031, a TRPA1 selective antagonist, attenuates inflammatory- and neuropathy-induced mechanical hypersensitivity

Molecular Pain, 2008

Background: Safe and effective treatment for chronic inflammatory and neuropathic pain remains a ... more Background: Safe and effective treatment for chronic inflammatory and neuropathic pain remains a key unmet medical need for many patients. The recent discovery and description of the transient receptor potential family of receptors including TRPV1 and TRPA1 has provided a number of potential new therapeutic targets for treating chronic pain. Recent reports have suggested that TRPA1 may play an important role in acute formalin and CFA induced pain. The current study was designed to further explore the therapeutic potential of pharmacological TRPA1 antagonism to treat inflammatory and neuropathic pain.

Research paper thumbnail of Uncontrollable Stimulation Undermines Recovery after Spinal Cord Injury

Journal of Neurotrauma, 2004

Prior studies have shown that neurons within the spinal cord are sensitive to response-outcome re... more Prior studies have shown that neurons within the spinal cord are sensitive to response-outcome relations, a form of instrumental learning. Spinally transected rats that receive shock to one hind leg learn to maintain the leg in a flexed position that minimizes net shock exposure (controllable shock). Prior exposure to uncontrollable stimulation (intermittent shock) inhibits this spinally mediated learning.

Research paper thumbnail of Instrumental learning within the spinal cord: underlying mechanisms and implications for recovery after injury

Behavioral and …, 2006

that how one answers this question has important implications for our views of learning, the regu... more that how one answers this question has important implications for our views of learning, the regulation of behavior, and the recovery of function after injury.

Research paper thumbnail of Instrumental learning within the spinal cord: V. Evidence the behavioral deficit observed after noncontingent nociceptive stimulation reflects an intraspinal modification

Behavioural Brain Research, 2003

Spinally transected rats given leg shock whenever one hindlimb is extended learn to maintain the ... more Spinally transected rats given leg shock whenever one hindlimb is extended learn to maintain the leg in a flexed position, which minimizes net shock exposure. Yoked rats, that receive an equal amount of shock independent of leg position (noncontingent shock), do not exhibit an increase in flexion duration. Yoked rats also fail to learn when response contingent shock is applied to the previously shocked leg, a behavioral deficit that resembles learned helplessness. This deficit could reflect either a peripheral (e.g. muscle fatigue) or central effect. Experiment 1 showed that spinalized rats given noncontingent shock to one hind limb fail to learn when response-contingent shock is applied to the contralateral leg. Experiment 2 demonstrated that blocking the afferent input to the spinal cord, by cutting the sciatic nerve, blocked the development of the deficit. Experiment 3 found that intrathecal lidocaine has a protective effect and prevents the deficit. These findings suggest that noncontingent nociceptive stimulation induces an intraspinal modification that undermines behavioral potential.

Research paper thumbnail of Two chronic motor training paradigms differentially influence acute instrumental learning in spinally transected rats

Behavioural Brain Research, 2007

The effect of two chronic motor training paradigms on the ability of the lumbar spinal cord to pe... more The effect of two chronic motor training paradigms on the ability of the lumbar spinal cord to perform an acute instrumental learning task was examined in neonatally (postnatal day 5; P5) spinal cord transected (i.e., spinal) rats. At ∼P30, rats began either unipedal hindlimb stand training (Stand-Tr; 20-25 min/day, 5 days/week), or bipedal hindlimb step training (Step-Tr; 20 min/day; 5 days/week) for 7 weeks. Non-trained spinal rats (Non-Tr) served as controls. After 7 weeks all groups were tested on the flexor-biased instrumental learning paradigm. We hypothesized that Step-Tr rats would exhibit an increased capacity to learn the flexor-biased task relative to Non-Tr subjects, as locomotion involves repetitive training of the tibialis anterior (TA), the ankle flexor whose activation is important for successful instrumental learning, and (2) Stand-Tr rats would exhibit a deficit in acute motor learning, as unipedal training activates the ipsilateral ankle extensors, but not flexors. Results showed no differences in acute learning potential between Non-Tr and Step-Tr rats, while the Stand-Tr group showed a reduced capacity to learn the acute task. Further investigation of the Stand-Tr group showed that, while both the ipsilateral and contralateral hindlimbs were significantly impaired in their acute learning potential, the contralateral, untrained hindlimbs exhibited significantly greater learning deficits. These results suggest that different types of chronic peripheral input may have a significant impact on the ability to learn a novel motor task, and demonstrate the potential for experience-dependent plasticity in the spinal cord in the absence of supraspinal connectivity.

Research paper thumbnail of Pain in a Balance: Noxious Events Engage Opposing Processes That Concurrently Modulate Nociceptive Reactivity

Behavioral Neuroscience, 2004

Studies have shown that noxious cutaneous stimulation engages physiologically different antinocic... more Studies have shown that noxious cutaneous stimulation engages physiologically different antinociceptive systems to inhibit a spinal reflex, tail withdrawal from radiant heat. Two experiments are reported that examine the relationship between the inhibition of the tail-flick response and brain-mediated responses to nociception. The induction of a spinally mediated antinociception was accompanied by an increase in latency to vocalize to a noxious thermal stimulus, suggesting pain inhibition. Physiological manipulations that eliminated the inhibition of the tail-flick reflex restored vocalization to thermal stimulation and revealed a concurrent sensitization that generally heightened behavioral reactivity. The results suggest that net pain is regulated by 2 opposing processes, a selective inhibition of nociceptive signals within the spinal cord and a general sensitization that heightens stimulus processing.

Research paper thumbnail of The Behavioral Deficit Observed Following Noncontingent Shock in Spinalized Rats Is Prevented by the Protein Synthesis Inhibitor Cycloheximide

Behavioral Neuroscience, 2004

Spinalized rats that receive shock when 1 hind limb is extended (contingent shock) exhibit an inc... more Spinalized rats that receive shock when 1 hind limb is extended (contingent shock) exhibit an increase in flexion duration, a simple form of instrumental learning. Rats that receive shock independent of leg position (noncontingent shock) do not exhibit an increase in flexion duration and fail to learn when tested with contingent shock 24 hr later. It appears that noncontingent shock induces an intraspinal modification that inhibits the capacity to learn. The authors propose that the mechanisms that underlie this effect depend on de novo protein synthesis. To evaluate this hypothesis, the authors gave spinalized rats the protein synthesis inhibitor cycloheximide (CXM) or saline intrathecally prior to, or immediately after, noncontingent shock exposure. Twenty-four hours later, rats were tested with contingent shock. Rats that received the vehicle and noncontingent shock failed to learn. CXM-treated shocked rats learned normally, suggesting that the learning deficit depends on protein synthesis within the spinal cord.

Research paper thumbnail of Instrumental Learning Within the Rat Spinal Cord: Localization of the Essential Neural Circuit

Behavioral Neuroscience, 2005

Following spinal transection of the upper thoracic spinal cord, male Sprague-Dawley rats given le... more Following spinal transection of the upper thoracic spinal cord, male Sprague-Dawley rats given legshock whenever a hindlimb is extended learn to maintain the leg in a flexed position. The region of the cord that mediates this instrumental learning was isolated using neuroanatomical tracing, localized infusion of lidocaine, and surgical transections. DiI and Fluoro-Gold microinjection at the site of shock application labeled motor neuron bodies of lamina IX in the lower lumbar region. Local application of the Na ϩϩ channel blocker lidocaine disrupted learning when it was applied over a region extending from the lower lumbar (L3) to upper sacral (S2) cord. The drug had no effect rostral or caudal to this region. Surgical transections as low as L4 had no effect on learning. Learning also survived a dual transection at L4 and S3, but not L4 and S2. The results suggest that the essential neural circuit lies between L4 and S3.

Research paper thumbnail of Instrumental learning within the spinal cord: IV. Induction and retention of the behavioral deficit observed after noncontingent shock

Behavioral Neuroscience, 2002

Research paper thumbnail of Shock-induced hyperalgesia: II. Role of the dorsolateral periaqueductal gray

Behavioral Neuroscience, 1999

Research paper thumbnail of Increases in the activated forms of ERK 1/2, p38 MAPK, and CREB are correlated with the expression of at-level mechanical allodynia following spinal cord injury

Experimental Neurology, 2006

Rats given moderate spinal cord injury (SCI) display increases in the expression of the activated... more Rats given moderate spinal cord injury (SCI) display increases in the expression of the activated form of the transcription factor cyclic AMP responsive element binding protein (CREB) in spinal segments of dermatomes corresponding to permanent mechanical allodynia, a model of chronic central neuropathic pain (CNP; (Crown, E.. Upregulation of the phosphorylated form of CREB in spinothalamic tract cells following spinal cord injury: relation to central neuropathic pain. Neurosci. Lett. 384, 139-144)). Given that not all rats that receive moderate SCI develop CNP, the current study was designed to further analyze changes in persistent CREB activation and in the activation state of upstream intracellular signaling cascades (e.g., mitogen-activated protein kinases [MAPKs]) in populations of rats that receive SCI and weeks later develop CNP and rats that receive SCI but do not develop CNP. The results indicate that activated kinases such as pERK 1/2, p-p38 MAPK, but not pJNK, are upregulated in injured rats that develop CNP as compared to injured rats that fail to develop CNP. In addition, the current results replicated our previous finding that activated CREB is upregulated following SCI, however, only in SCI rats that developed CNP. Taken together, these results indicate that activation of intracellular signaling cascades traditionally associated with long-term potentiation and memory is associated with the expression of chronic CNP following SCI.