Role of imidazoline receptors in the anti-aversive properties of clonidine during opiate withdrawal in rats.

Clonidine is used as a treatment for heroin addiction. Previous studies have reported that clonidine attenuated conditioned place aversion (CPA) to naloxone-precipitated opiate withdrawal by acting on alpha2 adrenoceptors (alpha2R). However, clonidine acts as a partial agonist both at alpha2R and at imidazoline-1 receptors (I1Rs). The current study was designed to determine the role of I1R in the induction of naloxone-induced CPA in morphine-dependent rats. Morphine dependence was induced by subcutaneous implantation of morphine pellets. Morphine-dependent rats were tested in a three-chamber place-aversion apparatus. A range of agonists were chosen on the basis of their differential selectivity for alpha2R and I1R. As expected, pretreatment with clonidine prevented naloxone-induced CPA. By contrast, pretreatment with a selective alpha2R agonist (UK14304) failed to prevent the CPA. We then tested whether the high affinity of clonidine for I1R was responsible for the difference between these two alpha2R agonists. Rilmenidine (a mixed alpha2R/I1R agonist) attenuated aversion to opiate withdrawal in a dose-dependent manner. The action of clonidine on I1R was studied by co-administering clonidine with RX821002, a specific alpha2R antagonist. Co-treatment with RX821002 and clonidine blocked naloxone-induced CPA. These results indicate that the pharmacologically protective effects of clonidine on naloxone-induced CPA are related to actions on I1RS as well as alpha2Rs.