Molecular Mechanisms of Opioid Receptor-dependent Signaling and Behavior

Abstract

Opioid receptors have been targeted for the treatment of pain and related disorders for thousands of years, and remain the most widely used analgesics in the clinic. Mu (μ), kappa (κ), and delta (δ) opioid receptors represent the originally classified receptor subtypes, with opioid receptor like-1 (ORL1) being the least characterized. All four receptors are G-protein coupled, and activate inhibitory G-proteins. These receptors form homo- and hetereodimeric complexes, signal to kinase cascades, and scaffold a variety of proteins. In this review, we discuss classical mechanisms and developments in understanding opioid tolerance, opioid receptor signaling, and highlight advances in opioid molecular pharmacology, behavioral pharmacology, and human genetics. We put into context how opioid receptor signaling leads to the modulation of behavior with the potential for therapeutic intervention. Finally, we conclude that there is a continued need for more translational work on opioid receptors in vivo.

Involvement of Opioid System, TRPM8, and ASIC Receptors in Antinociceptive Effect of <em>Arrabidaea Brachypoda </em>(DC) Bureau

“…The opioid system acts by modulating the ion channels of the neurons in the descending pathways of nociception. When activated, the opioid receptors inhibit the influx of Ca 2+ in the presynaptic fibers, reducing the release of neurotransmitters, while hyperpolarizing the postsynaptic fibers due to K + efflux [30]. TRPM8 is a major cold and cooling transduction channel in mammalian sensory neurons and it is strongly activated by the cool-mimetic chemical menthol and by physical cooling [20].…”

Analgesics Use in Dentistry

“…These responses are mainly mediated from Gi proteins by closing N-type voltageoperated calcium channels and opening calcium-dependent inwardly rectifying potassium channels, which result in hyperpolarization and reduction in neuronal excitability. Another mediated effect is the decrease of intracellular cAMP, which modulates the release of substance P, a nociceptive neurotransmitter [48].…”

An Integrated Quantitative Proteomics and Systems Biology Approach to Explore Synaptic Protein Profile Changes During Morphine Exposure

“…Following acute morphine administration, activation of opioid receptors results primarily in the inhibition of synaptic transmission, ultimately leading to the well-characterized analgesia induced by morphine. As a result of their G i /G o coupling, activation of opioid receptors by acute administration of morphine or other opiates leads to an inhibition of adenylyl cyclase activity (Duman et al, 1988;Taussig et al, 1993), and consequently to a decrease in cyclic AMP (cAMP) levels (Minneman and Iversen, 1976;Al-Hasani and Bruchas, 2011) and to decreased activity of protein kinase A (PKA). In addition, acute administration of morphine or other opiates results in diminished presynaptic Ca 2 þ conductance (Lovinger et al, 2003;Lovinger, 2010), increased K þ conductance, and hyperpolarization of the pre-and postsynaptic terminals (Faber and Sah 2004), along with an overall reduction in both neurotransmitter release and postsynaptic neurotransmitter signaling (Law et al, 2000).…”

“…Currently, it is thought that the facilitated activity of AC, PKA, and cAMP in response to chronic morphine exposure, while representing a homeostatic compensatory mechanism (Nestler, 1996;Al-Hasani and Bruchas, 2011), may also contribute to the etiology of opiate addiction (Terwilliger et al, 1991;Nestler, 2001). This is thought to be because of changes in gene expression; chronic exposure to morphine has been shown to induce the activity of a number of transcription factors.…”