Comparison of the antinociceptive and antispastic action of (−)-baclofen after systemic and intrathecal administration in intact, acute and chronic spinal rats

Abstract

Baclofen is particularly effective in treating spasticity of spinal origin in humans. However, most investigations of this drug in animals have only assessed its antinociceptive effect, presumably because of the difficulty in developing animal models of spasticity. This study attempted to evaluate both, the antinociceptive and antispastic action of (−)-baclofen (the more active enantiomer) by incorporating the chronic spinal preparation, in which spasticity gradually develops following spinal transection. Separate groups of intact, acute (1 day) or chronic (20–25 days) spinal rats were pretested on the nociceptive tail-flick (TF) assay prior to either subcutaneous (SC; 1–30 mg/kg) or intrathecal (IT; 0.1–12 μg) injection of (−)-baclofen and retested at specific post-injection intervals. Hindlimb spasticity was elicited in chronic spinal rats by mechanical stimulation to the abdomen. Because the clinical use of baclofen generally involves chronic administration, both responses were tested for 3 successive days to assess tolerance. Results confirmed the analgesic effect of SC and IT (−)-baclofen in intact rats. As previously reported, the antinociceptive effect of IT (−)-baclofen was increased in acute spinal rats. However, three weeks after spinalization there was a profound decrease in this response. In contrast, antinociception produced by SC (−)-baclofen was reduced in acute and chronic spinal rats compared to intact animals; but there was no difference between the acute and chronic conditions. In spite of this differential decrease in antinociception after IT, relative to SC, administration, both routes of administration produced an antispastic effect in chronic spinal rats. There was no antinociceptive tolerance to SC administration and only minimal tolerance to IT (−)-baclofen (in intact rats); the antispastic effect did not become tolerant. A peripheral action might explain the dichotomy between SC and IT (−)-baclofen in regard to antinociception. However, further research is needed to determine why both routes of administration were effective against spasticity while only SC (−)-baclofen retained an antinociceptive action in chronic spinal rats.