The ambiguities of opioid tolerance mechanisms: barriers to pain therapeutics or new pain therapeutic possibilities.

Identification of adaptations to chronic morphine that are causally associated with opioid tolerance formation has long been intensely pursued by the opioid research community. There is an impressive array of components of signaling pathways that are influenced by chronic opioid administration. This underscores the importance to tolerance mechanisms of the complex interplay of cellular adaptations that are downstream from the opioid receptor. A major impetus for this research remains the need to develop opioid agonists that are potent and efficacious activators of analgesic mechanisms without triggering opioid tolerance-producing adaptations. Implicit in most models of opioid tolerance is that their underlying mechanisms are invariant and independent of the system in which they have been observed. Reports that prior acute morphine treatment and pain could influence tolerance mechanisms were not understood on mechanistic levels and, consequently, were not incorporated into commonly used models of opioid tolerance. The recent demonstration that adenylyl cyclase/cAMP-related cellular adaptations to chronic morphine depend on cell state demonstrates that ongoing cell physiology is a critical determinant of tolerance mechanisms. The plasticity and pliability of cellular adaptations that mediate tolerance formation indicate that mechanisms underlying opioid analgesic tolerance could be a moving target. Although this might represent a daunting barrier to developing antitolerance pharmacotherapies, appreciation of this complexity could lead to the development of new pharmacotherapeutic approaches.