title: Intrathecal baclofen down-regulates GABAB receptors in the rat substantia gelatinosa.
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 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.
authors.affiliation: Department of Neurosurgery, Rush Medical College, Chicago, Illinois.
authors.forename: J S
authors.initials: JS
authors.lastname: Kroin
authors.forename: G D
authors.initials: GD
authors.lastname: Bianchi
authors.forename: R D
authors.initials: RD
authors.lastname: Penn
mesh_terms: D000818:Animals; D001345:Autoradiography; D001418:Baclofen / Q000008:administration & dosage* / Q000494:pharmacology; D015536:Down-Regulation; D007260:Infusion Pumps; D007278:Injections, Spinal; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D018079:Receptors, GABA / Q000378:metabolism*; D013376:Substantia Gelatinosa / Q000378:metabolism*; D013997:Time Factors
chemical_list: D018079:Receptors, GABA; D001418:Baclofen