Exposure to intermittent nociceptive stimulation under pentobarbital anesthesia disrupts spinal cord function in rats

Washburn, Stephanie N.; Patton, Brianne C.; Ferguson, Adam R.; Hudson, Kara; Grau, James W.

doi:10.1007/s00213-007-0707-1

Cited by 19 publications

(27 citation statements)

References 56 publications

(76 reference statements)

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“…The traditional model of central sensitization focuses on NMDAR-mediated plasticity within the spinal cord and assumes that this process is regulated by both descending circuits and GABAergic inhibition (Gjerstad et al, 2001; Gwak and Hulsebosch, 2011; Washburn et al, 2007; Woolf, 2004). This general framework is supported by 20+ years of research.…”

Section: Discussionmentioning

confidence: 99%

“…A similar pattern was observed by Weng et al (1998) who showed that bicuculline blocks central sensitization in halothane anaesthetized arthritic rats. Evidence suggests that pentobarbital anesthesia disrupts brain-dependent processes that normally counter the development of central sensitization (Washburn et al, 2007). This effect has been linked to serotonergic fibers that descend through the dorsolateral funiculus (DLF) (Crown and Grau, 2005).…”

Section: Discussionmentioning

confidence: 99%

“…Supporting this, research has shown that peripheral stimulation at an intensity that engages C-fibers induces a lasting NMDAR-dependent modification of spinal circuits [long-term potentiation (LTP)], central sensitization, and an inhibition of adaptive plasticity in spinally transected subjects (Sandkuhler, 2000). This same stimulation has little effect on spinal circuits in uninjured subjects (Gjerstad et al, 2001; Washburn et al, 2007), implying that the loss of descending fibers places the caudal tissue in a vulnerable state that fosters the development of central sensitization.…”

Section: Introductionmentioning

confidence: 99%

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Acute spinal cord injury (SCI) transforms how GABA affects nociceptive sensitization

Huang

Lee

Murphy

et al. 2016

Experimental Neurology

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Noxious input can sensitize pain (nociceptive) circuits within the spinal cord, inducing a lasting increase in spinal cord neural excitability (central sensitization) that is thought to contribute to chronic pain. The development of spinally-mediated central sensitization is regulated by descending fibers and GABAergic interneurons. The current study provides evidence that spinal cord injury (SCI) transforms how GABA affects nociceptive transmission within the spinal cord, recapitulating an earlier developmental state wherein GABA has an excitatory effect. In spinally transected rats, noxious electrical stimulation and inflammation induce enhanced mechanical reactivity (EMR), a behavioral index of nociceptive sensitization. Pretreatment with the GABAA receptor antagonist bicuculline blocked these effects. Peripheral application of an irritant (capsaicin) also induced EMR. Both the induction and maintenance of this effect were blocked by bicuculline. Cellular indices of central sensitization [c-fos expression and ERK phosphorylation (pERK)] were also attenuated. In intact (sham operated) rats, bicuculline had the opposite effect. Pretreatment with a GABA agonist (muscimol) attenuated nociceptive sensitization in intact, but not spinally injured, rats. The effect of SCI on GABA function was linked to a reduction in the Cl− transporter, KCC2, leading to a reduction in intracellular Cl− that would attenuate GABA-mediated inhibition. Pharmacologically blocking the KCC2 channel (with i.t. DIOA) in intact rats mimicked the effect of SCI. Conversely, a pharmacological treatment (bumetanide) that should increase intracellular Cl− levels blocked the effect of SCI. The results suggest that GABAergic neurons drive, rather than inhibit, the development of nociceptive sensitization after spinal injury.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Acute spinal cord injury (SCI) transforms how GABA affects nociceptive sensitization

Huang

Lee

Murphy

et al. 2016

Experimental Neurology

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“…When exposed to uncontrollable shock, the spinal cord develops a lasting impairment in behavioral plasticity (Grau et al, 1998; Crown and Grau, 2001; Crown et al, 2002b; Ferguson et al, 2003; Joynes and Grau, 2004; Patton et al, 2004; Ferguson et al, 2006; Washburn et al, 2007). Pharmacological activation of mGluRs mimicked the effects of uncontrollable shock, whereas mGluR antagonism at the time of training facilitated learning.…”

Section: Discussionmentioning

confidence: 99%

Group I Metabotropic Glutamate Receptors Control Metaplasticity of Spinal Cord Learning through a Protein Kinase C-Dependent Mechanism

Ferguson

Bolding²,

Huie³

et al. 2008

J. Neurosci.

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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 (Ͼ24 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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“…In this study, we employed the tailshock paradigm to also assess the effect of nociceptive stimulation on locomotor recovery following SCI. Subjects were treated with electrical stimulation 24 hours after surgery (modified from Washburn et al, 2007). They were loosely restrained in Plexiglas tubes as previously described (Crown et al, 2002a; Grau et al, 2004).…”

Section: Methodsmentioning

confidence: 99%

Intermittent noxious stimulation following spinal cord contusion injury impairs locomotor recovery and reduces spinal brain-derived neurotrophic factor–tropomyosin-receptor kinase signaling in adult rats

et al. 2011

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Intermittent nociceptive stimulation following a complete transection or contused spinal cord injury (SCI) has been shown to exert several short and long lasting negative consequences. These include maladaptive spinal plasticity, enhanced mechanical allodynia and impaired functional recovery of locomotor and bladder functions. The neurotrophin, brain derived neurotrophic factor (BDNF) has been shown to play an important role in adaptive plasticity and also to restore functions following SCI. This suggests that the negative behavioral effects of shock are most likely related to corresponding changes in BDNF spinal levels. In this study we investigated the cellular effects of nociceptive stimulation in contused adult rats focusing on BDNF, its receptor, TrkB, and the subsequent downstream signaling system. The goal was to determine whether the behavioral effect of stimulation is associated with concomitant cellular changes induced during the initial post-injury period. Quantitative RT-PCR and western blotting were used to assess changes in the mRNA and/or protein levels of BDNF, TrkB and the downstream signaling proteins CAMKII and ERK1/2 at 1 hour, 24 hours and 7 days following administration of intermittent noxious shock to the tail of contused subjects. In addition, recovery of locomotor function (BBB score) was assessed daily for the first week post injury. The results showed that, while nociceptive stimulation failed to induce any changes in gene expression at 1 hour, it significantly reduced the expression of BDNF, TrkB, ERK2 and CAMKII, at 24 hours. In general, changes in gene expression were spatially localized to the dorsal spinal cord. In addition, locomotor recovery was impaired by shock. Evidence is also provided suggesting that shock engages a neuronal circuitry without having any negative effects on neuronal survival at 24 hours. These results suggest that nociceptive activity following SCI decreases BDNF and TrkB levels, which may significantly contribute to diminished functional recovery.

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Exposure to intermittent nociceptive stimulation under pentobarbital anesthesia disrupts spinal cord function in rats

Cited by 19 publications

References 56 publications

Acute spinal cord injury (SCI) transforms how GABA affects nociceptive sensitization

Acute spinal cord injury (SCI) transforms how GABA affects nociceptive sensitization

Group I Metabotropic Glutamate Receptors Control Metaplasticity of Spinal Cord Learning through a Protein Kinase C-Dependent Mechanism

Intermittent noxious stimulation following spinal cord contusion injury impairs locomotor recovery and reduces spinal brain-derived neurotrophic factor–tropomyosin-receptor kinase signaling in adult rats

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