Trafficking of central opioid receptors and descending pain inhibition

The delta-opioid receptor (DOR) belongs to the superfamily of G-protein-coupled receptors (GPCRs) with seven transmembrane domains, and its membrane trafficking is regulated by intracellular sorting processes involving its C-tail motifs, intracellular sorting proteins, and several intracellular signaling pathways. In the quiescent state, DOR is generally located in the intracellular compartments in central neurons. However, chronic stimulation, such as chronic pain and sustained opioid exposure, may induce membrane trafficking of DOR and its translocation to surface membrane. The emerged functional DOR on cell membrane is actively involved in pain modulation and opioid analgesia. This article reviews current understanding of the mechanisms underlying GPCRs and DOR membrane trafficking, and the analgesic function of emerged DOR through membrane trafficking under certain pathophysiological circumstances

Increased glutamate synaptic transmission in the nucleus raphe magnus neurons from morphine-tolerant rats

Currently, opioid-based drugs are the most effective pain relievers that are widely used in the treatment of pain. However, the analgesic efficacy of opioids is significantly limited by the development of tolerance after repeated opioid administration. Glutamate receptors have been reported to critically participate in the development and maintenance of opioid tolerance, but the underlying mechanisms remain unclear. Using whole-cell voltage-clamp recordings in brainstem slices, the present study investigated chronic morphine-induced adaptations in glutamatergic synaptic transmission in neurons of the nucleus raphe magnus (NRM), a key supraspinal relay for pain modulation and opioid analgesia. Chronic morphine significantly increased glutamate synaptic transmission exclusively in one class of NRM cells that contains μ-opioid receptors in a morphine-tolerant state. The adenylyl cyclase activator forskolin and the cAMP analog 8-bromo-cAMP mimicked the chronic morphine effect in control neurons and their potency in enhancing the glutamate synaptic current was significantly increased in neurons from morphine-tolerant rats. MDL12330a, an adenylyl cyclase inhibitor, and H89, a protein kinase A (PKA) inhibitor, reversed the increase in glutamate synaptic transmission induced by chronic morphine. In addition, PMA, a phorbol ester activator of protein kinase C (PKC), also showed an increased potency in enhancing the glutamate synaptic current in these morphine-tolerant cells. The PKC inhibitor GF109203X attenuated the chronic morphine effect. Taken together, these results suggest that chronic morphine increases presynaptic glutamate release in μ receptor-containing NRM neurons in a morphine-tolerant state, and that the increased glutamate synaptic transmission appears to involve an upregulation of both the cAMP/PKA pathway and the PKC pathway. This glutamate-mediated activation of these NRM neurons that are thought to facilitate spinal pain transmission may contribute to the reduced opioid analgesia during opioid tolerance

Mechanisms of membrane trafficking for G-protein-coupled receptors (GPCRs)

<p><b>Copyright information:</b></p><p>Taken from "Trafficking of central opioid receptors and descending pain inhibition"</p><p>http://www.molecularpain.com/content/3/1/37</p><p>Molecular Pain 2007;3():37-37.</p><p>Published online 4 Dec 2007</p><p>PMCID:PMC2219988.</p><p></p> Upon agonist binding (), a GPCR, including the delta-opioid receptor (DOR), is phosphorylated by GPCR kinases (GRK) (), binds to proteins AP-2 and arrestin (), and undergoes the process of internalization via endocytosis through clathrin-coated pit (). Once internalized, the receptor is subjected to highly regulated sorting processes and is targeted either to endosomes in the recycling pathway () for membrane insertion, or to lysosomes for degradation through the degradation pathway (). DOR is synthesized in the endoplasmic reticulum (ER) (), then transported to the trans-Golgi network () through ER-Golgi complex, and becomes a mature receptor. Matured DOR is normally targeted intracellularly in large dense-core vesicles () as intracellular pool of DOR ready for membrane trafficking and insertion. Chronic pain conditions induce the release of a number of inflammatory mediators, which activate corresponding receptors () and increase intracellular calcium concentration, causing the membrane trafficking of DOR. Persistent stimulation of mu-opioid receptors (MOR) by chronic opioids () can induce the membrane trafficking of intracellular DOR and bring out functional DOR through yet unknown mechanisms

Rewarding Morphine-Induced Synaptic Function of δ-Opioid Receptors on Central Glutamate Synapses

The rewarding effect of opioids, the driving force for compulsive behaviors of opioid abuse and addiction, is primarily mediated by the μ-opioid receptor. However, the role of the δ-opioid receptor (DOR) in opioid reward and addiction is still poorly understood. The recently discovered adaptive DOR property of exocytotic translocation in sensory neurons after chronic opioid exposure provides a new avenue of conceptual thoughts to exploring the DOR function in this psychoneurological disease. In this study, we investigated potential adaptive function of DOR in neurons of the central nucleus of the amygdala (CeA), a forebrain structure increasingly recognized for mediating stimulus reward learning in drug addiction. Using whole-cell recordings in CeA slices, we found that in rats displaying morphine-induced behavior of conditioned place preference, a behavioral measure of drug reward, the overall synaptic strength of glutamate synapses in CeA neurons was significantly enhanced. The selective DOR agonist [d-Pen2,d-Pen5]-enkephalin, having no apparent effect on glutamatergic excitatory postsynaptic current (EPSC) in neurons from control rats, produced a significant, dose-dependent inhibition of the synaptic current in neurons from those morphine-treated rats. Detailed analyses of EPSC properties revealed that DOR activation inhibited the EPSC by reducing presynaptic release of glutamate, indicating functional DOR emerging on presynaptic glutamate terminals. The morphine treatment also significantly increased DOR proteins in CeA preparations of synaptosomes. These findings provide functional evidence for an adaptive modulation by presynaptic DOR of a key synaptic activity altered by morphine, thus implying likely important involvement of DOR in opioid reward and addiction

Genetic variations that influence paclitaxel pharmacokinetics and intracellular effects that may contribute to chemotherapy-induced neuropathy: A narrative review

Taxanes, particularly paclitaxel and docetaxel, are chemotherapeutic agents commonly used to treat breast cancers. A frequent side effect is chemotherapy-induced peripheral neuropathy (CIPN) that occurs in up to 70% of all treated patients and impacts the quality of life during and after treatment. CIPN presents as glove and stocking sensory deficits and diminished motor and autonomic function. Nerves with longer axons are at higher risk of developing CIPN. The causes of CIPN are multifactorial and poorly understood, limiting treatment options. Pathophysiologic mechanisms can include: (i) disruptions of mitochondrial and intracellular microtubule functions, (ii) disruption of axon morphology, and (iii) activation of microglial and other immune cell responses, among others. Recent work has explored the contribution of genetic variation and selected epigenetic changes in response to taxanes for any insights into their relation to pathophysiologic mechanisms of CIPN20, with the hope of identifying predictive and targetable biomarkers. Although promising, many genetic studies of CIPN are inconsistent making it difficult to develop reliable biomarkers of CIPN. The aims of this narrative review are to benchmark available evidence and identify gaps in the understanding of the role genetic variation has in influencing paclitaxel's pharmacokinetics and cellular membrane transport potentially related to the development of CIPN

sj-docx-1-tct-10.1177_15330338221127169 - Supplemental material for A Multimodal Approach to Discover Biomarkers for Taxane-Induced Peripheral Neuropathy (TIPN): A Study Protocol

Supplemental material, sj-docx-1-tct-10.1177_15330338221127169 for A Multimodal Approach to Discover Biomarkers for Taxane-Induced Peripheral Neuropathy (TIPN): A Study Protocol by Anukriti Sharma, PhD, Ken B. Johnson, MD, Bihua Bie, MD, PhD, Emily E. Rhoades, PhD, Alper Sen, MD, Yuri Kida, MS, Jennifer Hockings, PharmD, PhD, Alycia Gatta, BS, Jacqueline Davenport, MS, Connie Arcangelini, BS, Jennifer Ritzu, BS, Jennifer DeVecchio, BS, Ron Hughen, BS, Mei Wei, MD, G. Thomas Budd, MD, N. Lynn Henry, MD, Charis Eng, MD, PhD, Joseph Foss, MD, and Daniel M. Rotroff, PhD in Technology in Cancer Research & Treatment</p