Effects of intrathecal α1- and α2-noradrenergic agonists and norepinephrine on locomotion in chronic spinal cats

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, alpha(1) and alpha(2) adrenoceptors. The aim of this study was to investigate the effects of selective alpha(1) and alpha(2) agonists in the initiation and modulation of locomotion in adult chronic cats in the early and late stages after complete transection at T-13 Five cats, chronically implanted with an intrathecal cannula and electromyographic (EMG) electrodes were used in this study. Noradrenergic drugs including alpha(2) agonists (clonidine, tizanidine, and oxymetazoline) and an antagonist, yohimbine, one alpha(1) 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 alpha(1) and alpha(2) 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 alpha(2) agonists were found to initiate locomotion, although their action had a different time course. The alpha(1) 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 alpha(1) antagonist prazosin. In late spinal cats, although alpha(2) agonists markedly increased the cycle duration and flexor muscle burst duration and decreased the weight support or extensor activity (effects blocked by an alpha(2) antagonist, yohimbine), alpha(1) agonist increased the weight support and primarily the extensor activity of the hindlimbs without markedly changing the timing of the step cycle. Although alpha(2) agonists, especially clonidine, markedly reduced the cutaneous excitability and augmented the foot drag, the alpha(1) 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 alpha(1) and alpha(2) 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.