Studies on the pharmacology of locomotion in adult chronic spinal cat

The goal of the present project was to study the enhancement of recovery of locomotion of the hindlimbs after spinalisation through training and/or pharmacological agents.; Locomotion has been shown to be generated by a locomotor circuitry within the spinal cord which normally interacts with peripheral afferents and descending inputs to adjust the pattern to changes of the environment or perturbations. Following a low thoracic complete spinal transection in adult cats, which eliminates all descending commands, cats initially loose their ability to support the weight of the hindquarters or walk on a treadmill. However, with time and especially locomotor training (practised stepping on a treadmill belt), spinal cats can recover the ability to fully support the weight of the hindquarters and walk on the treadmill with the hindlimbs which in a manner resembles the normal cat in many ways. This evolution after spinalisation implies that the spinal cord circuitry responsible for locomotion is capable of some plastic changes. It is not known, however, if locomotor training done sooner after spinalisation would further promote or accelerate the locomotor recovery process. The first series of experiments address this question. In order for locomotor training to be possible during the early post-spinalisation period (within the first week when the cat could not initiate any stepping), Clonidine, a noradrenergic agonist known to trigger locomotion, was given. Electromyogram (EMG) of the hindlimb muscles synchronized to video images of the hindlimbs during treadmill locomotion were recorded. We found that cats that received daily injection of Clonidine followed by early and daily locomotor training showed a progressive improvement of locomotion and an acceleration of recovery of locomotion (6--11 days) as compared to previously reported (3 weeks).; Another goal of this project was to investigate the specific roles of various pharmacological agents in enhancing locomotor recovery. In the literature, the noradrenergic system was the most effective neurotransmitter system among others (serotonergic, dopaminergic, or excitatory amino acids) in triggering locomotion in adult spinal cats soon after transection. For instance, Clonidine was shown to trigger locomotion soon after spinalisation and modulate the well established locomotor pattern in adult spinal cats by increasing the step cycle duration. While different types of noradrenergic drugs (alpha1- and alpha2-agonists) have been shown to be able to mediate different physiological effects, little information is available on the effects of noradrenergic agonists other than Clonidine. The second series of experiments therefore explored the role of two other alpha2-agonists (Tizanidine and Oxymetazoline), an alpha1-agonist (Methoxamine), and noradrenaline itself, on locomotion and reflex transmission in adult spinal cats using an intrathecal catheter. Selective alpha2- and alpha1-antagonists (Yohimbine and Prazosin) were also used to block the effects. We found that all alpha2-agonists initiated locomotion within the first week post transection, whereas the alpha1-agonist was less consistent. All alpha2-agonists reduced cutaneous excitability while alpha1-agonist increased the cutaneous excitability.; Therefore, our results obtained in cats would suggest that pharmacotherapy could be used as an adjunct to locomotor training to optimize the recovery of locomotion in patients soon after injury. It is also possible to incorporate the use of drugs in targeting specific postural and locomotor deficits as these drugs are capable of interacting with spinal locomotor center to affect locomotor ability, cutaneous reflex and muscle tonus.