Elsevier

Life Sciences

Volume 62, Issues 17–18, 27 March 1998, Pages 1525-1530
Life Sciences

Regulation of neurokinin-1 receptor expression by GABAB receptor agonists

https://doi.org/10.1016/S0024-3205(98)00101-5Get rights and content

Abstract

Activation of GABAB receptors produces analgesia in acute and chronic pain models. Data indicate that a possible mechanism for this effect is a GABAB receptor-induced blockade of neurokinin-1 (NK-1) receptor gene expression in the spinal cord. While much more potent GABAB receptor agonists (CGP 44532) have been developed, there is no information on their antinociceptive properties or their ability to influence NK-1 receptors. To address these issues, rats were treated with baclofen or CGP 44532 and tested for sedation, ataxia, and pain-related behaviors in a chronic pain model (formalin hindpaw injection). In a separate group of experiments the analgesic response to a single dose of CGP 44532 was tested prior, and subsequent to, its chronic administration. The results indicate that CGP 44532 is a substantially more potent analgesic than baclofen. In addition, after chronic administration baclofen was no longer capable of inducing analgesia or of inhibiting the increased expression of NK-1R mRNA and CGP 44532 was still fully effective in both regards. The results suggest that GABAB agonists could be clinically useful analgesics.

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    In view of these results, we studied the effects of prolonged treatments with these compounds on glucose homeostasis, since the inconsistencies surrounding chronic treatments with GABAB receptor agonists or antagonists have remained largely unresolved. Chronic administration of baclofen has been shown to decrease the number of GABAB receptors associated to the pharmacological effects of this agent (Enna et al., 1998; Malcangio et al., 1993) and also to induce the desensitization of the receptor without altering the mRNA expression of the GABAB subunits (Sands et al., 2003), while others reported lack of effects in different brain areas (Motohashi, 1992). Pratt et al. suggested an increase in the number of GABAB receptors in prefrontal cortex lamina I after repeated oral administration of 10 mg/kg baclofen, although not achieving statistical significance (Pratt and Bowery, 1993).

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