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

Bancroft

2017

Journal of Neurotrauma

Opioids are frequently used for the treatment of pain following spinal cord injury (SCI). Unfortunately, we have shown that morphine administered in the acute phase of SCI results in significant, adverse secondary consequences including compromised locomotor and sensory recovery. Similarly, we showed that selective activation of the j-opioid receptor (KOR), even at a dose 32-fold lower than morphine, is sufficient to attenuate recovery of locomotor function. In the current study, we tested whether activation of the KOR is necessary to produce morphine's adverse effects using norBinaltorphimine (norBNI), a selective KOR antagonist. Rats received a moderate spinal contusion (T12) and 24 h later, baseline locomotor function and nociceptive reactivity were assessed. Rats were then administered norBNI (0, 0.02, 0.08, or 0.32 lmol) followed by morphine (0 or 0.32 lmol). Nociception was reassessed 30 min after drug treatment, and recovery was evaluated for 21 days. The effects of norBNI on morphine-induced attenuation of recovery were dose dependent. At higher doses, norBNI blocked the adverse effects of morphine on locomotor recovery, but analgesia was also significantly decreased. Conversely, at low doses, analgesia was maintained, but the adverse effects on recovery persisted. A moderate dose of norBNI, however, adequately protected against morphine's adverse effects without eliminating its analgesic efficacy. This suggests that activation of the KOR system plays a significant role in the morphineinduced attenuation of recovery. Our research suggests that morphine, and other opioid analgesics, may be contraindicated for the SCI population. Blocking KOR activity may be a viable strategy for improving the safety of clinical opioid use.

Section: Figmentioning

confidence: 99%

Nor-Binaltorphimine Blocks the Adverse Effects of Morphine after Spinal Cord Injury

Bancroft

2017

Journal of Neurotrauma

Behavioural Brain Research

“…The question addressed in the present study, therefore, was whether bipedal step-training (StepTr) or unipedal hindlimb stand-training (Stand-Tr) in neonatal spinally transected rats changed the potential to perform a novel, acute instrumental spinal learning task relative to non-trained (Non-Tr) rats [3,4,6,7,25,27]. During the 30 min instrumental learning task, spinally transected rats receive shock to the tibialis anterior (TA) muscle whenever the leg is extended, and learn to maintain the leg in a flexed position, thereby minimizing net shock exposure [25].…”

Section: Introductionmentioning

confidence: 99%

Two chronic motor training paradigms differentially influence acute instrumental learning in spinally transected rats

Bigbee

Crown

Ferguson

et al. 2007

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/wk), or bipedal hindlimb step training (Step-Tr; 20 min/day; 5 days/wk) for 7 wks. Non-trained spinal rats (Non-Tr) served as controls. After 7 wks all groups were tested on the flexor-biased instrumental learning paradigm. We hypothesized that 1) 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 experiencedependent plasticity in the spinal cord in the absence of supraspinal connectivity.

“…Similarly, intrathecal lidocaine before uncontrollable shock blocks the induction of the deficit observed when subjects are tested 24 h later. 13 Neither lidocaine nor cutting the sciatic nerve eliminated the behavioral response (Crown et al; 11 Joynes et al; 13 Figures 5b and d). As generally assumed within FES paradigms, the electrical stimulation drives the motor response even though communication with the spinal cord has been disrupted -the stimulationinduced response does not reflect a spinally mediated withdrawal response.…”

Section: Learning Depends On Spinal Neuronsmentioning

confidence: 99%

“…In addition, cutting the sciatic nerve before administering uncontrollable stimulation to the same leg blocks the induction of the deficit when subjects are subsequently tested on the contralateral leg. 13 Pharmacological manipulations also implicate spinal neurons. If spinal neurons are anesthetized through the local (intrathecal) application of the Na þ channel blocker lidocaine, subjects fail to learn (Crown et al; 11 Figure 5c).…”

Section: Learning Depends On Spinal Neuronsmentioning

confidence: 99%

An animal model of functional electrical stimulation: evidence that the central nervous system modulates the consequences of training

Hook

Grau

2007

Spinal Cord

Study Design: Review of how spinal neurons can modulate the consequences of functional electrical stimulation (FES) in an animal model. Methods: Spinal effects of FES are examined in male Sprague-Dawley rats transected at the second thoracic vertebra. The rats are exposed to FES training 24-48 h after surgery. Experimental manipulations of stimulation parameters, combined with physiological and pharmacological procedures, are used to examine the potential role of spinal neurons. Results: The isolated spinal cord is inherently capable of learning the response-outcome relations imposed in FES training contingencies. Adaptive behavioral modifications are observed when an outcome (electrical stimulation) is contingent on a behavioral response. In contrast, a lack of correlation between the response and outcome in training produces a learning deficit in the spinal cord, rendering it incapable of adaptive learning for up to 48 h. The N-methyl-D-aspartic acid receptor appears to mediate both the adaptive plasticity and loss of plasticity, seen in this spinal model. Conclusion:The behavioral effects observed with FES therapies are not simply due to the direct (motor) consequences of stimulation elicited by the activation of efferent motor neurons and/or selected muscles. FES training has the capacity to shape inherent spinal circuits and to produce a long-lasting behavioral modification. Further understanding of the spinal mechanisms underlying adaptive behavioral modification will be integral for establishing functional neural connections in a regenerating spinal system.