| Agonists acting at a2 -adrenergic and opioid receptors share common signal transduction systems mediated through the inhibitory G proteins, the activation of which inhibit pain transmission. In addition, a2 -adrenergic and opioid receptor agonists interact synergistically when coadministered in the spinal cord. This property is important in clinical pain management because synergy-enabled decreases in analgesic dose may minimize side effects, and combination therapy may be advantageous in the treatment of chronic, opioid-insensitive pain states such as neuropathic pain. Insights into understanding the factors dictating the nature of drug interactions could therefore have broad implications for pain management.;Synergistic interactions between classes of agonists have been frequently reported in the literature, the conditions under which synergistic interactions occur remain largely unknown. It has been proposed that synergy between receptors sharing signal transduction systems cannot occur if the two receptor populations are anatomically co-localized. The goal of this study was therefore to determine if there is an anatomical basis for synergistic interactions between G protein-coupled receptors in the spinal cord.;In the first phase of this study, the relative role of the three a2 -adrenoceptor subtypes in spinal adrenergic analgesia and opioid synergy was assessed using genetically engineered mice. Second, the localization of the a2 -adrenoceptor subtypes in the spinal cord was investigated immunohistochemically using antisera developed specifically for this project. Third, the hypothesis that synergistic pairs will be localized on different synaptic compartments was examined by using double-label immunohistochemistry and confocal microscopy. Finally, the effect of peripheral nerve injury on the expression of several a2 -adrenergic and opioid receptor subtypes was evaluated.;We observed that synergictically interacting receptor pairs can be either differentially localized or highly co-localized. These findings suggest that the mechanisms underlying synergistic interactions between G protein coupled receptors are not dependent on specific arrangements of receptors in the spinal cord. These results suggest that the mechanisms underlying synergistic interactions between Gi/o-coupled receptors are more complex than was originally anticipated; differential localization is not an absolute requirement. |
