Selective antinociceptive effects of tizanidine (DS 103–282), a centrally acting muscle relaxant, on dorsal horn neurones in the feline spinal cord

Abstract

The effects of the centrally acting muscle relaxant tizanidine have been examined on the responses of laminae IV and V dorsal horn neurones to peripheral noxious and non-noxious stimuli in cats spinalized at Ll. 2 lontophoretic ejection of tizanidine near the cell bodies of the recorded neurones or more dorsally into laminae 11-HI resulted in a marked and prolonged depression of excitation of laminae IV and V neurones evoked by noxious stimuli. Spontaneous firing was also depressed in many neurones but responses to innocuous stimuli were unaffected. 3 Intravenous administration of tizanidine also produced a long lasting and selective reduction in responses of laminae IV and V neurones to noxious stimuli and depressed the long latency excitation of these neurones evoked by electrical stimulation of small diameter unmyelinated primary afferents. 4 In contrast to the selective antinociceptive effect of tizanidine, ejection of y-aminobutyric acid (GABA) near laminae IV and V neurones or isoguvacine into laminae II-I-I produced parallel reductions in responses to noxious and non-noxious stimuli. Furthermore, ejections of the excitant amino acid kainate into laminae II-III produced parallel enhancement of responses induced by both types of stimuli. 5 The site and mechanism of the antinociceptive action of tizanidine is not known but does not appear to involve an interaction with opiate receptors as it was not antagonized by naloxone. The possibility is discussed that tizanidine acts at synapses formed between excitatory interneurones in lamina II or III and laminae IV and V neurones, either interfering with transmitter release or its postsynaptic action. 6 The effects of iontophoretically administered tizanidine are quite distinct from those of baclofen, which produced non-selective depression of responses to both noxious and innocuous stimuli, but were similar to those of noradrenaline. This raises the possibility that noradrenaline and tizanidine may act at a common site in the spinal cord.

α2‐Agonists as analgesic agents

“…The first studies on this drug were carried out in beginning of 1980s, when the site and the mechanism of the antinociceptive action were still not known. 121,122 A few years later it was observed that the analgesic effect induced by tizanidine in the tail-flick test in mice was antagonized by the a 2 -adrenoceptor antagonist yohimbine, suggesting that the analgesia could be mediated by a 2 -adrenoceptors. 123 Asano and coworkers demonstrated that there is a good correlation between antinociceptive effect and binding affinity for tizanidine in the spinal cord and brain.…”

Traditional pharmacological treatments for spasticity part II: General and regional treatments

“…97,98 These findings have been bolstered by the observation that tizanidine has an antinociceptive effect in animal models. [99][100][101] Finally, tizanidine enhances vibratory inhibition of H reflex in humans and reduces abnormal co-contraction, effects which have been correlated with clinical improvements of spasticity in patients. 102…”

Pharmacokinetics of Orally Administered Tizanidine in Healthy Volunteers

“…In addition to its muscle relaxant action, tizanidine has an antinociceptive activity which is stronger than that of morphine and mediated by a non-opioid mechanism (Davies and Johnston, 1984; Kameyama et a/., 1985; Kameyama et al, 1986;Nabeshima et al, 1986). Recent studies have also demonstrated anticonvulsant properties of tizanidine in rodent and primate models of epilepsy (De Sarro et a/., 1984).…”