Mu-opioid receptors are widely distributed in the central and peripheral nervous system and upon activation have manifold actions including;depression of respiration, activation of the reward pathway, disruption of normal gastrointestinal motility and analgesia. Chronic administration of opioids results in a decline in the response (tolerance) the degree of which differs depending on the agonist and the measure under study. Analgesic tolerance to opioids limits the therapeutic efficacy. On the other hand, the development of tolerance in the gut is slow. The link between tolerance measured at the cellular and behavioral levels involves two general mechanisms, one involving a reduction of the receptor/effector coupling and the second results from homeostatic adaptations that counteract opioid signaling. Both mechanisms are initiated by agonist/receptor binding and contribute to behavioral tolerance. One repeatable and robust measure of opioid action in single cells is acute desensitization. This is an initial adaptive step in the pathway to cellular tolerance and is the subject of intense investigation. Most emphasis has centered on a model involving (1) agonist occupancy, (2) receptor phosphorylation by a G- protein Receptor Kinase and (3) arrestin binding. This proposal will study mu- opioid receptors directly using a kinetic approach. Experiments will test the hypothesis that opioid receptor desensitization results from an agonist dependent change in receptor conformation that has high affinity for agonist and is less functional. The experiments will go on to determine how this agonist dependent transition of the receptor is changed following chronic treatment of animals with morphine. The recognition and characterization of the high affinity conformation is a necessary step in developing new approaches to control the development of tolerance to opioids.
Opioids are used clinically for the treatment of acute and chronic pain. The development of tolerance is a limitation of these compounds. The results of this study will define the earliest agonist/receptor-dependent processes. Knowledge of these early events with acute application of agonists as well as the change in regulation following chronic treatment will facilitate the development of protocols for safe and effective treatment of pain.
|Williams, John T (2014) Desensitization of functional µ-opioid receptors increases agonist off-rate. Mol Pharmacol 86:52-61|
|Banghart, Matthew R; Williams, John T; Shah, Ruchir C et al. (2013) Caged naloxone reveals opioid signaling deactivation kinetics. Mol Pharmacol 84:687-95|
|Arttamangkul, Seksiri; Lau, Elaine K; Lu, Hsin-Wei et al. (2012) Desensitization and trafficking of ýý-opioid receptors in locus ceruleus neurons: modulation by kinases. Mol Pharmacol 81:348-55|
|Quillinan, Nidia; Lau, Elaine K; Virk, Michael et al. (2011) Recovery from mu-opioid receptor desensitization after chronic treatment with morphine and methadone. J Neurosci 31:4434-43|
|Matsui, Aya; Williams, John T (2011) Opioid-sensitive GABA inputs from rostromedial tegmental nucleus synapse onto midbrain dopamine neurons. J Neurosci 31:17729-35|
|Matsui, Aya; Williams, John T (2010) Activation of ýý-opioid receptors and block of Kir3 potassium channels and NMDA receptor conductance by L- and D-methadone in rat locus coeruleus. Br J Pharmacol 161:1403-13|
|Virk, Michael S; Arttamangkul, Seksiri; Birdsong, William T et al. (2009) Buprenorphine is a weak partial agonist that inhibits opioid receptor desensitization. J Neurosci 29:7341-8|
|Torrecilla, Maria; Quillinan, Nidia; Williams, John T et al. (2008) Pre- and postsynaptic regulation of locus coeruleus neurons after chronic morphine treatment: a study of GIRK-knockout mice. Eur J Neurosci 28:618-24|
|Virk, Michael S; Williams, John T (2008) Agonist-specific regulation of mu-opioid receptor desensitization and recovery from desensitization. Mol Pharmacol 73:1301-8|
|Dumont, E C; Rycroft, B K; Maiz, J et al. (2008) Morphine produces circuit-specific neuroplasticity in the bed nucleus of the stria terminalis. Neuroscience 153:232-9|
Showing the most recent 10 out of 43 publications