title: Molecular mechanisms of excitatory signaling upon chronic opioid agonist treatment.
abstract: Opioid receptor agonists mediate their analgesic effects by interacting with Gi/o protein-coupled opioid receptors. Acute treatment with opioid agonists is thought to mediate analgesia by hyperpolarization of presynatic neurons, leading to the inhibition of excitatory (pain) neurotransmitters release. After chronic treatment however, the opioid receptors gradually become less responsive to agonists, and increased drug doses become necessary to maintain the therapeutic effect (tolerance). Analgesic tolerance is the result of two, partially overlapping processes: a gradual loss of inhibitory opioid function is accompanied by an increase in excitatory signaling. Recent data indicate that chronic opioid agonist treatment simultaneously desensitizes the inhibitory-, and augments the stimulatory effects of the opioids. In the present paper we review the molecular mechanisms that may have a role in the augmentation of the excitatory signaling upon chronic opioid agonist treatment. We also briefly review our recent experimental data on the molecular mechanism of chronic opioid agonist-mediated functional sensitization of forskolin-stimulated cAMP formation, in a recombinant Chinese hamster ovary cell line stably expressing the human delta-opioid receptor (hDOR/CHO). To interpret the experimental data, we propose that chronic hDOR activaton leads to activation of multiple redundant signaling pathways that converge to activate the protein kinase, Raf-1. Raf-1 in turn phosphorylates and sensitizes the native adenylyl cyclase VI isoenzyme in hDOR/CHO cells, causing a rebound increase in forskolin-stimulated cAMP formation upon agonist withdrawal.
authors: Department of Pharmacology, The University of Arizona Health Sciences Center, Tucson, AZ 85724, USA.
authors: Eva V
authors: EV
authors: Varga
authors: Henry I
authors: HI
authors: Yamamura
authors: Marc K
authors: MK
authors: Rubenzik
authors: Dagmar
authors: D
authors: Stropova
authors: Edita
authors: E
authors: Navratilova
authors: William R
authors: WR
authors: Roeske
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007473:Ion Channels / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D011494:Protein Kinases / Q000378:metabolism / Q000502:physiology; D043562:Receptors, G-Protein-Coupled / Q000187:drug effects; D011957:Receptors, Opioid / Q000819:agonists*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D000701:Analgesics, Opioid; D007473:Ion Channels; D043562:Receptors, G-Protein-Coupled; D011957:Receptors, Opioid; D011494:Protein Kinases; D000262:Adenylyl Cyclases