Intrathecal baclofen down-regulates GABAB receptors in the rat substantia gelatinosa.

At present, it is not clear why drug tolerance develops in patients receiving intrathecal baclofen for the chronic treatment of spasticity of spinal origin. To investigate the mechanisms of tolerance to the gamma-aminobutyric acid (GABAB) agonist baclofen, rats were implanted with intrathecal catheters and continuously infused with either the drug or saline for 1, 3, or 7 days. The dose chosen, 1 microgram/hr, initially caused profound hindlimb motor weakness, but by Day 7 the rats had adapted to the drug and exhibited only minimal motor impairment. The animals were sacrificed on Day 1, 3, or 7 and quantitative autoradiography was used to determine the binding density and affinity of the GABAB receptors in the substantia gelatinosa of the lumbar spinal cord. After 1 day of drug infusion there was no change in binding parameters, but after 3 and especially after 7 days there was a significant decrease in the GABAB binding density (74% and 66%, respectively) in baclofen-treated rats as compared to saline-treated control rats. This GABAB receptor down-regulation correlated with tolerance to the motor weakness in the baclofen-treated animals and suggests that similar mechanisms contribute to drug tolerance in patients.