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

Abstract

Rationale-Spinal cord plasticity can be assessed in spinal rats using an instrumental learning paradigm in which subjects learn an instrumental response, hindlimb flexion, to minimize shock exposure. Prior exposure to uncontrollable intermittent stimulation blocks learning in spinal rats but has no effect if given before spinal transection, suggesting that supraspinal systems modulate nociceptive input to the spinal cord, rendering it less susceptible to the detrimental consequences of uncontrollable stimulation.Objective-The present study examines whether disrupting brain function with pentobarbital blocks descending inhibitory systems that normally modulate nociceptive input, making the spinal cord more sensitive to the adverse effect of uncontrollable intermittent stimulation. Materials and methods-MaleSprague-Dawley rats received uncontrollable intermittent stimulation during pentobarbital anesthesia after (experiment 1) or before (experiment 2) spinal cord transection. They were then tested for instrumental learning at a later time point. Experiment 3 examined whether these manipulations affected nociceptive (thermal) thresholds.Results-Experiment 1 showed that pentobarbital had no effect on the induction of the learning deficit after spinal cord transection. Experiment 2 showed that intact rats anesthetized during uncontrollable intermittent stimulation failed to learn when later transected and tested for instrumental learning. Experiment 3 found that uncontrollable intermittent stimulation induced an antinociception in intact subjects that was blocked by pentobarbital. Conclusions-The results suggest a surgical dose of pentobarbital (50 mg/kg) suppresses supraspinal (experiment 2) but not spinal (experiment 1) systems that modulate nociceptive input to the spinal cord by blocking the antinociception that is induced by this input (experiment 3).

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

“…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.…”

“…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).…”

“…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.…”

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

“…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.…”

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

“…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).…”