Pain relief: receptor dynamics at the single molecule level

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Chronic pain is no longer considered solely a symptom, but for complex and poorly understood reasons, is often self perpetuating and becomes like a disease unto itself. Among many therapeutic approaches to pain management, analgesic drug therapy continues to play a central role. Pure opioid agonists such as morphine remain the gold standard in pain pharmacotherapy, however toxicity of morphine therapy has limited its long term applicability. Better ways to understand how to improve tolerability of opioids and to predict which combinations of analgesics to offer, are urgently needed. Significantly, although morphine targets the same opioid receptor (mu opioid receptor, MOR) as endogenous opioids, it does not trigger the same mechanism for regeneration of free receptor at the cell's surface. It has been convincingly established that upon stimulation by morphine, MORs do not undergo the usual internalization, which is the first step in receptor regeneration. A drug cocktail induced correlation between the internalization rate of MOR and the dynamics of the NMD A receptor, DOR and/or beta-arrestin will provide an accurate assay for the potency of the cocktail. To observe these coupled dynamics, we will make real time molecular movies of the trafficking of ORs in response to various combinations of stimuli to OR and to the NMDA receptors. This will be accomplished using quantum dot labels and video-rate microscopy. We will use the simplest model biological system that provides correlation between biophysical response and known clinical outcome.