Broad opioid antagonism amplifies disruption of locomotor function following therapy-like hindlimb stretching in spinal cord injured rats.

STUDY DESIGN: Preclinical pilot study. OBJECTIVES: To test the hypothesis that spinal opioidergic circuitry contributes to muscle stretch-induced locomotor deficits. SETTING: Kentucky Spinal Cord Injury Research Center, Louisville, KY, USA. METHODS: A pilot study with eight female Sprague-Dawley rats that received 25 g-cm T10 contusion injuries and recovered for 5 weeks. Rats were divided into two groups with one group receiving subcutaneous injections of naltrexone dissolved in saline (15 mg/kg) or an equal volume of saline. Each group received a daily 24-minute stretching protocol during weeks 6, 8, and 11 post-injury. Locomotor function was assessed throughout using the BBB Open Field Locomotor Scale. RESULTS: Consistent with previous findings, stretching reduced locomotor function in both naltrexone and saline groups. However, the loss of locomotor function appeared earlier in the naltrexone group. Animals in both groups had a similar rate of recovery following the termination of stretching. Interestingly, the administration of naltrexone did not influence acute thermal cutaneous nociceptive responses as measured by a tail-flick assay but caused a significant increase in spasticity following stretch. CONCLUSIONS: The results of this study suggest that the endogenous opioid system plays a role in modulating the negative impact of muscle stretch on spinal cord motor circuitry that is vulnerable due to loss of descending input. The observed actions of the broad-spectrum opioid antagonist naltrexone imply that pharmaceuticals targeting the endogenous opioid system post-SCI may have unintended consequences.

Development of a Canine Rigid Body Musculoskeletal Computer Model to Evaluate Gait.

BACKGROUND: Kinematic and kinetic analysis have been used to gain an understanding of canine movement and joint loading during gait. By non-invasively predicting muscle activation patterns and forces during gait, musculoskeletal models can further our understanding of normal variability and muscle activation patterns and force profiles characteristic of gait. METHODS: Pelvic limb kinematics and kinetics were measured for a 2 year old healthy female Dachshund (5.4 kg) during gait using 3-D motion capture and force platforms. A computed tomography scan was conducted to acquire pelvis and pelvic limb morphology. Using the OpenSim modeling platform, a bilateral pelvic limb subject-specific rigid body musculoskeletal computer model was developed. This model predicted muscle activation patterns, muscle forces, and angular kinematics and joint moments during walking. RESULTS: Gait kinematics determined from motion capture matched those predicted by the model, verifying model accuracy. Primary muscles involved in generating joint moments during stance and swing were predicted by the model: at mid-stance the adductor magnus et brevis (peak activation 53.2%, peak force 64.7 N) extended the hip, and stifle flexor muscles (biceps femoris tibial and calcaneal portions) flexed the stifle. Countering vertical ground reaction forces, the iliopsoas (peak activation 37.9%, peak force 68.7 N) stabilized the hip in mid-stance, while the biceps femoris patellar portion stabilized the stifle in mid-stance and the plantar flexors (gastrocnemius and flexor digitorum muscles) stabilized the tarsal joint during early stance. Transitioning to swing, the iliopsoas, rectus femoris and tensor fascia lata flexed the hip, while in late swing the adductor magnus et brevis impeded further flexion as biceps femoris tibial and calcaneal portions stabilized the stifle for ground contact. CONCLUSION: The musculoskeletal computer model accurately replicated experimental canine angular kinematics associated with gait and was used to predict muscle activation patterns and forces. Thus, musculoskeletal modeling allows for quantification of measures such as muscle forces that are difficult or impossible to measure in vivo.

Reversible silencing of lumbar spinal interneurons unmasks a task-specific network for securing hindlimb alternation.

Neural circuitry in the lumbar spinal cord governs two principal features of locomotion, rhythm and pattern, which reflect intra- and interlimb movement. These features are functionally organized into a hierarchy that precisely controls stepping in a stereotypic, speed-dependent fashion. Here, we show that a specific component of the locomotor pattern can be independently manipulated. Silencing spinal L2 interneurons that project to L5 selectively disrupts hindlimb alternation allowing a continuum of walking to hopping to emerge from the otherwise intact network. This perturbation, which is independent of speed and occurs spontaneously with each step, does not disrupt multi-joint movements or forelimb alternation, nor does it translate to a non-weight-bearing locomotor activity. Both the underlying rhythm and the usual relationship between speed and spatiotemporal characteristics of stepping persist. These data illustrate that hindlimb alternation can be manipulated independently from other core features of stepping, revealing a striking freedom in an otherwise precisely controlled system.