Effects of intrathecal alpha1- and alpha2-noradrenergic agonists and norepinephrine on locomotion in chronic spinal cats

Abstract

Noradrenergic drugs, acting on alpha adrenoceptors, have been found to play an important role in the initiation and modulation of locomotor pattern in adult cats after spinal cord transection. There are at least two subtypes of alpha adrenoceptors, alpha1 and alpha2 adrenoceptors. The aim of this study was to investigate the effects of selective alpha1 and alpha2 agonists in the initiation and modulation of locomotion in adult chronic cats in the early and late stages after complete transection at T13. Five cats, chronically implanted with an intrathecal cannula and electromyographic (EMG) electrodes were used in this study. Noradrenergic drugs including alpha2 agonists (clonidine, tizanidine, and oxymetazoline) and an antagonist, yohimbine, one alpha1 agonist (methoxamine), and a blocker, prazosin, as well as norepinephrine were injected intrathecally. EMG activity synchronized to video images of the hindlimbs were recorded before and after each drug injection. The results show differential effects of alpha1 and alpha2 agonists in the initiation of locomotion in early spinal cats (i.e., in the first week or so when there is no spontaneous locomotion) and in the modulation of locomotion and cutaneous reflexes in the late-spinal cats (i.e., when cats have recovered spontaneous locomotion). In early spinal cats, all three alpha2 agonists were found to initiate locomotion, although their action had a different time course. The alpha1 agonist methoxamine induced bouts of nice locomotor activity in three spinal cats some hours after injection but only induced sustained locomotion in one cat in which the effects were blocked by the alpha1 antagonist prazosin. In late spinal cats, although alpha2 agonists markedly increased the cycle duration and flexor muscle burst duration and decreased the weight support or extensor activity (effects blocked by an alpha2 antagonist, yohimbine), alpha1 agonist increased the weight support and primarily the extensor activity of the hindlimbs without markedly changing the timing of the step cycle. Although alpha2 agonists, especially clonidine, markedly reduced the cutaneous excitability and augmented the foot drag, the alpha1 agonist was found to increase the cutaneous reflex excitability. This is in line with previously reported differential effects of activation of the two receptors on motoneuron excitability and reflex transmission. Noradrenaline, the neurotransmitter itself, increased the cycle duration and at the same time retained the cutaneous excitability, thus exerting both alpha1 and alpha2 effects. This work therefore suggests that different subclasses of noradrenergic drugs could be used to more specifically target aspects of locomotor deficits in patients after spinal injury or diseases.