Clonidine, a partial α2agonist, has been used empirically to alleviate opiate withdrawal symptoms, but the mechanism of its effects is not completely understood. We studied the interactions of opioid and adrenergic receptor agonists in the NG108‐15 cells, which are a model of opiate dependence. We determined that in these cells the adenylate cyclase (AC) [EC 4.6.1.1; ATP pyrophosphate‐lyase (cyclizing)] overshoot response to opioid or α2‐agonist withdrawal can be significantly attenuated or suppressed by the other agonist. Subsequently, the AC overshoot response can be triggered with the antagonist to the second agonist to which the cells were not dependent. These results demonstrate that convergent dependence to morphine and α2agonists can occur in a homogeneous cell population without neuronal loops. Therefore, the basic mechanisms that can account for convergent dependence in this model take place at the level of intracellular regulatory pathways that do not require neuronal networks.— Lee, S.; Rosenberg, C. R.; Musacchio, J. M. Cross‐dependence to opioid and α2‐adrenergic receptor agonists in NG108‐15 cells.FASEB J.2: 52‐55; 1988.