JPET #135533 PiP The ambiguities of opioid tolerance mechanisms: barriers to pain therapeutics or new pain therapeutic possibilities JPET #135533 PiP 2 Running title: Plasticity of tolerant mechanisms

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 acute prior morphine treatment and pain could influence tolerance mechanisms were not understood on mechanistic levels and consequently 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 indicates that mechanisms underlying opioid analgesic tolerance could be a moving target. While this might represent a daunting barrier to developing antitolerance pharmacotherapies, appreciation of this complexity could lead to the development of new pharmacotherapeutic approaches

Mu-opioid receptor splice variants: sex-dependent regulation by chronic morphine

Detail, glass entrance doors under circular canopy; A joint project of the Agency for Cultural Affairs and the National Museums Independent Administrative Institution, it stands on a site formerly occupied by a research facility of the University of Tokyo. The museum has an exhibition of 600 pieces, concentrating on 20th century painting and modern art. It has four stories above ground and one below. It contains an extensive Art Library with a special collection of exhibition catalogs. There is also an auditorium and a high-end restaurant (currently Brasserie Paul Bocuse Le Musée). Source: Wikipedia; http://en.wikipedia.org/wiki/Main_Page (accessed 8/2/2013