Dissociation of (−) Baclofen-Induced Effects on the Tail Withdrawal and Hindlimb Flexor Reflexes of Chronic Spinal Rats

Abstract

We previously reported that the antinociceptive effect of the GABA B receptor agonist, (−)baclofen, in chronic spinal rats depended on the route of administration. That is, subcutaneous (SC) injections significantly increased the latency of the thermally elicited tail withdrawal (tail flick, TF) reflex, whereas spinal (intrathecal, IT) injections did not. The present studies attempted to determine the reason for this differential response. The possible contribution of a peripheral component to the systemic effect was evaluated, but was not supported by negative results of intradermal (−)baclofen injections (50 and 500 μg) into the tail skin of chronic spinal rats. A spinal site of action was indicated when pretreatment with 30 μg, IT of the GABA B receptor antagonist, phaclofen, significantly reduced the antinociceptive effect of SC (−)baclofen in both chronic spinal (5 mg/kg) and intact rats (2 mg/kg). Moreover, direct IT injections of (−)baclofen in chronic spinal rats produced a modest, but statistically significant increase in TF latency at doses of 0.06, 0.12, 0.3, and 0.6 μg, but not 1.2 μg. In the same spinal preparation, the flexor response was significantly reduced by IT injection of 0.6 and 1.2 μg, but not lower doses of 0.3 and 0.12 μg. These results provide the first quantitative, electrophysiological evidence of an antispastic effect of IT (−)baclofen in an in vivo, unanesthetized animal model. Second, the data show a separation between an antinociceptive effect of low spinal doses and an antispastic/muscle relaxant effect at higher doses, which may account for the results of our prior report. Finally, the data are also consistent with behavioral reports of antiallodynic/analgesic effects of low-dose baclofen, and may be relevant to the electrophysiological evidence of a preferential presynaptic action of low-dose (−)baclofen at the primary afferent synapse.