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

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Abstract
✓ 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 µg/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 GABABreceptors in the substantia gelatinosa of the lumbar spinal cord. After I 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 GABABbinding density (74% and 66%, respectively) in baclofen-treated rats as compared to saline-treated control rats. This GABABreceptor 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.