Impact of Behavioral Control on the Processing of Nociceptive Stimulation

Abstract

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.

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

“…We previously investigated the effect of peripheral nociceptive stimulation on spinal plasticity and functional recovery following SCI [31,38]. In adult rats with a complete spinal transection, noxious input derived from electrical stimulation or peripheral inflammation, inhibited beneficial plasticity producing a spinal learning deficit that resembles learned helplessness [18,45].…”

Challenges and opportunities of sensory plasticity after SCI

“…The spinal cord is capable of interpreting afferent input to learn a task and to counter perturbing forces or avoid obstacles placed in the path of hindlimbs stepping on a treadmill, and even retaining this information for a short time without reinforcement (Zhong et al, 2012). This collective work suggests that the spinal cord is capable of learning (see also Ferguson et al, 2012a,b; Grau et al, 2012), and may be capable of processes akin to formation of short- and long-term memory.…”

“…Another approach has examined the principles of learning that may be at play in the spinal cord (Ferguson et al, 2012a,b; Grau et al, 2012), with important concepts emerging about extrinsic factors interfering with successful spinal learning (i.e., training). Given the relative success of activity-based therapies in both animal and human experiments and the significant effort and resources dedicated to optimizing these approaches for clinical gain, we must also identify factors that inhibit recovery (e.g., Caudle et al, 2011; Ferguson et al, 2012a,b).…”

What Is Being Trained? How Divergent Forms of Plasticity Compete To Shape Locomotor Recovery after Spinal Cord Injury

“…[105][106][107][108] In the context of SCI, intense peripheral nociceptive input has been shown to affect not only sensory systems, but motor plasticity as well. 82,[109][110][111][112][113] To test the effect of nociceptive input on sensory and motor recovery, Grau and colleagues produced a thoracic spinal contusion injury in rats, followed by administration of an experimentally controlled uncontrollable nociceptive stimulus (electrical shock to the tail sufficient to drive C-fiber activation). They found that as little as 6 min of C-fiber-strength intermittent nociceptive stimulation could induce sensory dysfunction (hyperalgesia and mechanical allodynia), produce acute learning deficits on an adaptive motor training task, and undermine locomotor recovery for at least 6 weeks.…”