Effects of Intrathecal a1- and a2-Noradrenergic Agonists and Norepinephrine on Locomotion in Chronic Spinal Cats

Chau, Connie, Hugues Barbeau, and Serge Rossignol. Effects review, see Rossignol 1996). For example, in in vitro neonaof intrathecal a1and a2-noradrenergic agonists and norepinephrine tal rat preparation, locomotor activity have been found to be on locomotion in chronic spinal cats. J. Neurophysiol. 79: 2941– released by EAA (Cazalets et al. 1990; Kudo and Yamada 2963, 1998. Noradrenergic drugs, acting on a adrenoceptors, have 1987; Smith and Feldman 1987), serotonin (Cazalets et al. been found to play an important role in the initiation and modula1992; Cowley and Schmidt 1994; Kiehn and Kjaerulff tion of locomotor pattern in adult cats after spinal cord transection. 1996), and cholinergic drugs (Katakura and Chandler There are at least two subtypes of a adrenoceptors, a1 and a2 1991). In chronic spinal cats, among the different pharmacoadrenoceptors. The aim of this study was to investigate the effects logical agents, noradrenergic drugs were found to be the of selective a1 and a2 agonists in the initiation and modulation of locomotion in adult chronic cats in the early and late stages after most effective in initiating locomotion (Barbeau and Rossigcomplete transection at T13. Five cats, chronically implanted with nol 1991; Barbeau et al. 1987). The importance of the noradan intrathecal cannula and electromyographic (EMG) electrodes renergic system has been shown by early studies from were used in this study. Noradrenergic drugs including a2 agonists Lundberg and colleagues (Anden et al. 1966a,b; Jankowska (clonidine, tizanidine, and oxymetazoline) and an antagonist, yoet al. 1967) who demonstrated the ability of noradrenergic himbine, one a1 agonist (methoxamine), and a blocker, prazosin, agents to activate neuronal circuits that could be responsible as well as norepinephrine were injected intrathecally. EMG activity for locomotor function. They showed that intravenous injecsynchronized to video images of the hindlimbs were recorded betion of the noradrenergic precursor, dihydroxy phenylalanine fore and after each drug injection. The results show differential effects of a1 and a2 agonists in the initiation of locomotion in early (DOPA) inhibited the transmission of short latency respinal cats ( i.e., in the first week or so when there is no spontaneous sponses from the flexor reflex afferent (FRA) but released locomotion) and in the modulation of locomotion and cutaneous long-latency and long-duration discharges not normally reflexes in the late-spinal cats ( i.e., when cats have recovered sponfound in acute spinal cats. These late discharges often taneous locomotion). In early spinal cats, all three a2 agonists evolved as sequences of rhythmically alternating activity were found to initiate locomotion, although their action had a difbetween flexors and extensors reminiscent of stepping. It ferent time course. The a1 agonist methoxamine induced bouts of was suggested indeed that the interneuronal circuitry genernice locomotor activity in three spinal cats some hours after injecating the late discharges evoked after DOPA could be retion but only induced sustained locomotion in one cat in which sponsible for generating locomotion. This was pursued by the effects were blocked by the a1 antagonist prazosin. In late spinal cats, although a2 agonists markedly increased the cycle duraGrillner and Zangger (1979) who showed that a detailed tion and flexor muscle burst duration and decreased the weight locomotor rhythm can be generated by the neuronal circuitry support or extensor activity (effects blocked by an a2 antagonist, within the spinal cord itself. Indeed, after the injection of yohimbine), a1 agonist increased the weight support and primarily the noradrenergic precursor (DOPA) and nialamide (a the extensor activity of the hindlimbs without markedly changing monoamine oxidase inhibitor) , a pattern of rhythmic alterthe timing of the step cycle. Although a2 agonists, especially cloninating discharges in antagonist hindlimb muscle nerves was dine, markedly reduced the cutaneous excitability and augmented observed in acute spinal and curarized cat. DOPA (intravethe foot drag, the a1 agonist was found to increase the cutaneous nously) has been postulated to mediate its effects through the reflex excitability. This is in line with previously reported differential effects of activation of the two receptors on motoneuron excitactivation of noradrenergic receptors (Anden et al. 1966a,b) . ability and reflex transmission. Noradrenaline, the neurotransmitter Using a noradrenergic receptor agonist (clonidine) , Forssitself, increased the cycle duration and at the same time retained berg and Grillner (1973) demonstrated the ability of noradthe cutaneous excitability, thus exerting both a1 and a2 effects. renergic drugs to initiate locomotion. They showed in acute This work therefore suggests that different subclasses of noradrenspinal cats (Th12) that after an intravenous injection of clonergic drugs could be used to more specifically target aspects of idine, cats could walk with both hindlimbs when placed on locomotor deficits in patients after spinal injury or diseases. a moving treadmill belt. They suggested that the descending noradrenergic system could ‘‘release’’ the spinal circuitry for stepping. These results were supported by work in our I N T R O D U C T I O N