REGULATION OF NEUROKININ-1 RECEPTOR EXPRESSION BY GABA(B) RECEPTOR AGONISTS

Activation of GABA(B) receptors produces analgesia in acute and chroni c pain models. Data indicate that a possible mechanism for this effect is a GABA(B) receptor-induced blockade of neurokinin-1 (NK-1) recepto r gene expression in the spinal cord. While much more potent GABA(B) r eceptor agonists (CGP 44532) have been developed, there is no informat ion on their antinociceptive properties or their ability to influence NK-1 receptors. To address these issues, rats were treated with baclof en or CGP 44532 and tested for sedation, ataxia, and pain-related beha viors in a chronic pain model (formalin hindpaw injection). In a separ ate group of experiments the analgesic response to a single dose of CG P 44532 was tested prior, and subsequent to, its chronic administratio n. The results indicate that CGP 44532 is a substantially more potent analgesic than baclofen. In addition, after chronic administration bac lofen was no longer capable of inducing analgesia or of inhibiting the increased expression of NK-1R mRNA and CGP 44532 was still fully effe ctive in both regards. The results suggest that GABA(B) agonists could be clinically useful analgesics.