Concomitant depression of locus coeruleus neurons and of flexor reflexes by an alpha 2-adrenergic agonist in rats: a possible mechanism for an alpha 2-mediated muscle relaxation

Abstract

The alpha 2-agonist tizanidine, clinically used as an antispastic drug, also strongly reduces polysynaptic flexor reflexes. The hypothesis was tested that the noradrenergic coerulespinal system exerts a tonic facilitation on spinal reflexes and that the depressant effects of tizanidine may be explained by an alpha 2-mediated autoinhibition of the tonic activity of locus coeruleus neurons, resulting in a disfacilitation of the spinal reflexes. The following results support this working hypothesis: (1) systemic injections of tizanidine markedly decreased the spontaneous activity of locus coeruleus neurons, but not of non-locus coeruleus neurons. The alpha 2-antagonist yohimbine reversed this effect. (2) The time course of diminished locus coeruleus activity paralleled that of depressed flexor reflexes. (3) Flexor reflexes were also markedly depressed by the alpha 1-adrenergic antagonist prazosin, administered alone, which is in line with the proposition that the noradrenergic system exerts a tonic facilitation on spinal neurons by way of alpha 1-adrenergic receptor activation. (4) Flexor reflexes were facilitated by conditioning microstimulation of locus coeruleus neurons, and this effect was reversed by prazosin. (5) Flexor reflexes significantly diminished in size following placement of an irreversible lesion in the ipsilateral locus coeruleus. Although these results strongly support the above hypothesis regarding a descending modulatory function of the descending locus coeruleus system on spinal reflexes, possible additional mechanisms, perhaps also involving the ascending projection of the locus coeruleus to supraspinal motor structures, remain to be elucidated.