REVIEW ARTICLE published: 10 August 2012 doi: 10.3389/fphys.2012.00262 Impact of behavioral control on the processing of nociceptive stimulation James W. Grau 1*, J. Russell Huie 2, Sandra M. Garraway 1, Michelle A. Hook 1, Eric D. Crown3, Kyle M. Baumbauer 4, Kuan H. Lee 1, Kevin C. Hoy 1 and Adam R. Ferguson2 1 Cellular and Behavioral Neuroscience, Department of Psychology, Texas A&M University, College Station, TX, USA 2 Brain and Spinal Injury Center, Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA 3 Abbott Laboratories, Chicago, IL, USA 4 Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA Edited by: How nociceptive signals are processed within the spinal cord, and whether these signals Jeffrey Petruska, University of lead to behavioral signs of neuropathic pain, depends upon their relation to other events Louisville, USA and behavior. Our work shows that these relations can have a lasting effect on spinal plas- Reviewed by: Lorne Mendell, Stony Brook ticity, inducing a form of learning that alters the effect of subsequent nociceptive stimuli. University, USA The capacity of lower spinal systems to adapt, in the absence of brain input, is examined Veronica Tom, Drexel University in spinally transected rats that receive a nociceptive shock to the tibialis anterior muscle College of Medicine, USA of one hind leg. If shock is delivered whenever the leg is extended (controllable stimu- *Correspondence: lation), it induces an increase in flexion duration that minimizes net shock exposure. This James W. Grau, Psychology Department, Texas A&M University, learning is not observed in subjects that receive the same amount of shock independent College Station, TX 77843-4235, USA. of leg position (uncontrollable stimulation). These two forms of stimulation have a lasting, e-mail: [email protected] 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 nocicep- tive 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. Keywords: plasticity, instrumental conditioning, learning, spinal cord injury, nociception, BDNF,allodynia, recovery of function INTRODUCTION effect that helps to ameliorate the effect of spinal injury. Con- In the absence of spinal injury, the processing of afferent pain versely, a lack of behavioral control can enhance the adverse effect (nociceptive) signals within the spinal cord is regulated by the of nociceptive stimulation and promote the development of neu- brain through descending pathways (Sandkühler and Liu, 1998; ropathic pain, an issue that is discussed in our companion paper Gjerstad et al., 2001). In the presence of prolonged nociceptive (Ferguson et al.,under review). Here we focus on the processes that stimulation, these descending brain pathways can exert a protec- underlie the abstraction of behavioral control and the mechanisms tive effect that dampens neural excitability and, thereby, prevents that underlie its long-term benefit. the sensitization of nociceptive mechanisms (central sensitization) Because this work relies on concepts developed within the field and the development of neuropathic pain (Davies et al., 1983; of learning, we will first provide an overview of some essential Faden et al., 1988; Eaton et al., 1997; Hains et al., 2002). Spinal concepts in learning and their application to spinal cord plastic- cord injury (SCI) removes this protective effect, allowing spinal ity and behavioral rehabilitation. We will then discuss evidence systems to react in an unbridled way to on-going afferent input. In that a nociceptive stimulus has divergent effects depending upon the absence of the brain’s oversight,how nociceptive signals impact whether it is controllable (response-contingent) or uncontrol- spinal systems will depend upon intrinsic mechanisms. We will lable (non-contingent). We will present evidence that a history show that these intraspinal systems are tuned to detect whether of behavioral control can reduce the adverse effects of nociceptive the nociceptive signal is related to the performance of a particular stimulation and counter the development of neuropathic pain. We response (controllable stimulation) and that allowing behavioral will conclude by reviewing evidence that the beneficial effect of control can engage processes that exert a protective/restorative controllable stimulation depends on brain-derived neurotrophic www.frontiersin.org August 2012 | Volume 3 | Article 262 | 1 Grau et al. Behavioral control and nociceptive plasticity factor (BDNF) and will present a model that integrates these isolated spinal mechanisms could exhibit this type of learning and observations. We propose that behavioral control acts to gate how because instrumental learning would seem especially relevant to afferent nociceptive signals are processed, and that this determines behavioral rehabilitation after SCI. whether the stimulus has an adaptive or maladaptive effect. A key question at this juncture is: why focus on learning? How is this relevant to the recovery of function after SCI? To under- LEARNING AND REHABILITATION stand the importance of learning, consider the primary aim of Our work is guided by an understanding of how systems adapt behavioral rehabilitation – to “retrain” the injured system. At its (i.e., how they learn) in the intact organism. Learning from this heart, behavioral rehabilitation involves a set of tasks designed to perspective represents a form of plasticity, where the effect of a promote the performance of behaviors that will enhance function stimulus (S), a response (R), or an outcome (O), depends upon and the patient’s well being. To the extent that these procedures whether the event (the S, R, or O) has previously occurred and yield a lasting effect, they involve a form of learning, and to the its relation to other events (Domjan, 2010). Within this struc- extent this learning depends on having experienced a particular ture, learning is thought of as a process, a mechanism that detects R-O relation, they involve instrumental conditioning. The import and encodes on-going events and their relation to past experience. of these observations is enhanced by the recognition that behav- Memory represents the preservation of this information over time. ioral rehabilitation remains the most effective treatment for the Within this rubric, we use the term outcome to refer to stim- restoration of function after injury. ulus events that follow a R. If instituting a relationship between a Learning will likely also prove essential to medical treatments particular R and an O brings about a change in the R, the under- designed to foster neural growth to bridge an injury, because lying process is sometimes referred to as reinforcement and the O encouraging axon elongation is only part of the story. Once the a reinforcer. For example, if a rat is placed in a situation wherein injury is spanned, the pattern of synaptic connectivity must be pressing a bar yields a food pellet, the bar-press corresponds to tuned to promote adaptive processes and avoid maladaptive out- the R and the food is the O. If this contingency brings about an comes (e.g., neuropathic pain). Just as experience helps to shape increase in responding, it is commonly said that the presentation the pattern of connectivity during development, rewiring spinal of food reinforced bar pressing behavior. circuits will require procedures that promote adaptive learning. A potential source of confusion stems from the fact that an O is a stimulus event and, when its stimulus properties (e.g., intensity, SPINALLY MEDIATED LEARNING duration) are of concern, may be referred to as such. But more Our claim is that behavioral rehabilitation has a lasting effect often, the term S is used to refer to events that signal whether a because it encourages a form of learning and that this process particular R-O relation is in effect or to stimulus events that occur occurs, in part, within the spinal cord. In subsequent sections, we irrespective of any particular behavioral R. For example, presenta- bolster this claim with physiological and pharmacological stud- tion of a S alone might bring about a reduction (habituation) or ies examining the underlying mechanisms. As we will see, this increase (sensitization) in the behavioral R elicited by the S. Alter- work suggests that behavioral control may gate nociceptive signals natively, interposing a relationship between two stimuli [usually within the dorsal spinal cord and thereby determine whether stim- called the conditioned stimulus (CS) and unconditioned stimu- ulation has an adaptive