Identification of a novel spinal dorsal horn astroglial D-amino acid oxidase-hydrogen peroxide pathway involved in morphine antinociceptive tolerance.
TL;DR: For the first time, the authors identify a novel spinal astroglial DAAO–hydrogen peroxide pathway that is critically involved in the initiation and maintenance of morphine antinociceptive tolerance, and suggest that this pathway is of potential utility for the management of morphine tolerance and chronic pain.
Abstract: Background: D-Amino acid oxidase (DAAO) is a flavin adenine dinucleotide-dependent peroxisomal flavoenzyme which is almost exclusively expressed within astrocytes in the spinal cord. DAAO catalyzes oxidation of D-amino acids to hydrogen peroxide, which is a stable and less active reactive oxygen species, and may represent a final form of reactive oxygen species. This study tested the hypothesis that the spinal astroglial DAAO–hydrogen peroxide pathway plays an important role in the development of morphine antinociceptive tolerance. Methods: Rat and mouse formalin, hot-plate, and tail-flick tests were used, and spinal DAAO expression and hydrogen peroxide level were measured. Sample size of animals was six in each study group. Results: Subcutaneous and intrathecal DAAO inhibitors, including 5-chloro-benzo[d]isoxazol-3-ol, AS057278, and sodium benzoate, completely prevented and reversed morphine antinociceptive tolerance in the formalin, hot-plate, and tail-immersion tests, with a positive correlation to their DAAO inhibitory activities. Intrathecal gene silencers, small interfering RNA/DAAO and small hairpin RNA/DAAO, almost completely prevented morphine tolerance. Intrathecal 5-chloro-benzo[d]isoxazol-3-ol and small interfering RNA/DAAO completely prevented increased spinal hydrogen peroxide levels after chronic morphine treatment. Intrathecal nonselective hydrogen peroxide scavenger phenyl-tert-N-butyl nitrone and the specific hydrogen peroxide catalyst catalase also abolished established morphine tolerance. Spinal dorsal horn astrocytes specifically expressed DAAO was significantly up-regulated, accompanying astrocyte hypertrophy after chronic morphine treatment. Conclusions: For the first time, the authors’ result identify a novel spinal astroglial DAAO–hydrogen peroxide pathway that is critically involved in the initiation and maintenance of morphine antinociceptive tolerance, and suggest that this pathway is of potential utility for the management of morphine tolerance and chronic pain.
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TL;DR: The results illustrate a novel spinal dorsal horn microglial GLP-1R/β-endorphin inhibitory pathway in a variety of pain hypersensitivity states that potently alleviated formalin, peripheral nerve injury, bone cancer, and diabetes-induced hypers sensitivity states.
Abstract: This study aims to identify the inhibitory role of the spinal glucagon like peptide-1 receptor (GLP-1R) signaling in pain hypersensitivity and its mechanism of action in rats and mice. First, GLP-1Rs were identified to be specifically expressed on microglial cells in the spinal dorsal horn, and profoundly upregulated after peripheral nerve injury. In addition, intrathecal GLP-1R agonists GLP-1(7-36) and exenatide potently alleviated formalin-, peripheral nerve injury-, bone cancer-, and diabetes-induced hypersensitivity states by 60-90%, without affecting acute nociceptive responses. The antihypersensitive effects of exenatide and GLP-1 were completely prevented by GLP-1R antagonism and GLP-1R gene knockdown. Furthermore, exenatide evoked β-endorphin release from both the spinal cord and cultured microglia. Exenatide antiallodynia was completely prevented by the microglial inhibitor minocycline, β-endorphin antiserum, and opioid receptor antagonist naloxone. Our results illustrate a novel spinal dorsal horn microglial GLP-1R/β-endorphin inhibitory pathway in a variety of pain hypersensitivity states.
99 citations
TL;DR: The results suggest that geniposide and its iridoid analogs produce antinociception during persistent pain by activating the spinal GLP-1Rs and that the iridoids represented by genipOSide are orthosteric agonists of GLP -1Rs that function similarly in humans and rats and presumably act at the same binding site as exendin(9-39).
75 citations
Cites background or methods from "Identification of a novel spinal do..."
...The rat formalin test was performed as previously described (Gong et al., 2011a, 2014b)....
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...In our previous study, the ED50 value for exenatide spinal analgesia in the formalin-induced tonic pain was 2.5 ng (0.6 pmol) (Gong et al., 2014a)....
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...Our results suggested that the activation of the spinal GLP-1Rs by peptidic agonists leads to specific antinociception in chronic pain hypersensitivity states, notably refractory neuropathic pain, cancer pain and painful diabetic neuropathy (Gong et al., 2014a)....
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...Geniposide 100% reverses hydrogen peroxide oxidative damage and its maximal spinal antinociception of formalin pain is between 60 and 80%, which identical to the action of exenatide and GLP-1(7-36) (Gong et al., 2014a)....
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...The mouse formalin test was performed as previously described (Gong et al., 2014b, 2012)....
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TL;DR: The known properties of human DAAO suggest that its activity must be finely tuned to fulfill a main physiological function such as the control of D-serine levels in the brain as well as the role of post-translational modifications on its main biochemical properties at the cellular level.
Abstract: D-Amino acid oxidase (DAAO) is an FAD-containing flavoenzyme that catalyzes with absolute stereoselectivity the oxidative deamination of all natural D-amino acids, the only exception being the acidic ones. This flavoenzyme plays different roles during evolution and in different tissues in humans. Its three-dimensional structure is well conserved during evolution: minute changes are responsible for the functional differences between enzymes from microorganism sources and those from humans. In recent years several investigations focused on human DAAO, mainly because of its role in degrading the neuromodulator D-serine in the central nervous system. D-Serine is the main coagonist of N-methyl D-aspartate receptors, i.e., excitatory amino acid receptors critically involved in main brain functions and pathologic conditions. Human DAAO possesses a weak interaction with the FAD cofactor; thus, in vivo it should be largely present in the inactive, apoprotein form. Binding of active-site ligands and the substrate stabilizes flavin binding, thus pushing the acquisition of catalytic competence. Interestingly, the kinetic efficiency of the enzyme on D-serine is very low. Human DAAO interacts with various proteins, in this way modulating its activity, targeting, and cell stability. The known properties of human DAAO suggest that its activity must be finely tuned to fulfill a main physiological function such as the control of D-serine levels in the brain. At present, studies are focusing on the epigenetic modulation of human DAAO expression and the role of post-translational modifications on its main biochemical properties at the cellular level.
59 citations
Cites background from "Identification of a novel spinal do..."
...In this case, by inhibiting DAAO activity, a decrease in the production of spinal H2O2 levels is apparent (Lu et al., 2012; Gong et al., 2014)....
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TL;DR: It is reported that intrathecal IL-10 injection dose dependently attenuated mechanical allodynia and thermal hyperalgesiain male and female neuropathic rats, and revealed that IL- 10 produced antinociception through spinal microglial β-endorphin expression, but not inhibition of neuro inflammation.
Abstract: Interleukin 10 (IL-10) is antinociceptive in various animal models of pain without induction of tolerance, and its mechanism of action was generally believed to be mediated by inhibition of neuroinflammation. Here we reported that intrathecal IL-10 injection dose dependently attenuated mechanical allodynia and thermal hyperalgesiain male and female neuropathic rats, with ED50 values of 40.8 ng and 24 ng, and Emax values of 61.5% MPE and 100% MPE in male rats. Treatment with IL-10 specifically increased expression of the β-endorphin (but not prodynorphin) gene and protein in primary cultures of spinal microglia but not in astrocytes or neurons. Intrathecal injection of IL-10 stimulated β-endorphin expression from microglia but not neurons or astrocytes in both contralateral and ipsilateral spinal cords of neuropathic rats. However, intrathecal injection of the β-endorphin neutralizing antibody, opioid receptor antagonist naloxone, or μ-opioid receptor antagonist CTAP completely blocked spinal IL-10-induced mechanical antiallodynia, while the microglial inhibitor minocycline and specific microglia depletor reversed spinal IL-10-induced β-endorphin overexpression and mechanical antiallodynia. IL-10 treatment increased spinal microglial STAT3 phosphorylation, and the STAT3 inhibitor NSC74859 completely reversed IL-10-increased spinal expression of β-endorphin and neuroinflammatory cytokines and mechanical antiallodynia. Silence of the Bcl3 and Socs3 genes nearly fully reversed IL-10-induced suppression of neuroinflammatory cytokines (but not expression of β-endorphin), although it had no effect on mechanical allodynia. In contrast, disruption of the POMC gene completely blocked IL-10-stimulated β-endorphin expression and mechanical antiallodynia, but had no effect on IL-10 inhibited expression of neuroinflammatory cytokines. Thus this study revealed that IL-10 produced antinociception through spinal microglial β-endorphin expression, but not inhibition of neuroinflammation.
48 citations
TL;DR: This paper is the thirty-eighth consecutive installment of the annual review of research concerning the endogenous opioid system and summarizes papers published during 2015 that studied the behavioral effects of molecular, pharmacological and genetic manipulation of opioid peptides, opioid receptors, opioid agonists and opioid antagonists.
41 citations
References
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TL;DR: Biochemical and physiological characterization of catalases from many different organisms has revealed a surprisingly wide range ofCatalatic efficiencies, despite similar sequences.
Abstract: More than 300 catalase sequences are now available, divided among monofunctional catalases (> 225), bifunctional catalase-peroxidases (> 50) and manganese-containing catalases (> 25). When combined with the recent appearance of crystal structures from at least two representatives from each of these groups (nine from the monofunctional catalases), valuable insights into the catalatic reaction mechanism in its various forms and into catalase evolution have been gained. The structures have revealed an unusually large number of modifications unique to catalases, a result of interacting with reactive oxygen species. Biochemical and physiological characterization of catalases from many different organisms has revealed a surprisingly wide range of catalatic efficiencies, despite similar sequences. Catalase gene expression in micro-organisms generally is controlled either by sensors of reactive oxygen species or by growth phase regulons, although the detailed mechanisms vary considerably.
1,477 citations
TL;DR: The present studies suggest that NMDA receptors may be important in the development of opiate tolerance and dependence.
Abstract: The N-methyl-D-aspartate (NMDA) subtype of the glutamate receptor is an important mediator of several forms of neural and behavioral plasticity. The present studies examined whether NMDA receptors might be involved in the development of opiate tolerance and dependence, two examples of behavioral plasticity. The noncompetitive NMDA receptor antagonist MK-801 attenuated the development of tolerance to the analgesic effect of morphine without affecting acute morphine analgesia. In addition, MK-801 attenuated the development of morphine dependence as assessed by naloxone-precipitated withdrawal. These results suggest that NMDA receptors may be important in the development of opiate tolerance and dependence.
1,192 citations
TL;DR: D-serine is an endogenous modulator of the glycine site of NMDA receptors and fully occupies this site at some functional synapses and greatly attenuates NMDA receptor-mediated neurotransmission as assessed by using whole-cell patch-clamp recordings or indirectly by using biochemical assays of the sequelae of NMda receptor- mediated calcium flux.
Abstract: Functional activity of N-methyl-d-aspartate (NMDA) receptors requires both glutamate binding and the binding of an endogenous coagonist that has been presumed to be glycine, although d-serine is a more potent agonist. Localizations of d-serine and it biosynthetic enzyme serine racemase approximate the distribution of NMDA receptors more closely than glycine. We now show that selective degradation of d-serine with d-amino acid oxidase greatly attenuates NMDA receptor-mediated neurotransmission as assessed by using whole-cell patch–clamp recordings or indirectly by using biochemical assays of the sequelae of NMDA receptor-mediated calcium flux. The inhibitory effects of the enzyme are fully reversed by exogenously applied d-serine, which by itself did not potentiate NMDA receptor-mediated synaptic responses. Thus, d-serine is an endogenous modulator of the glycine site of NMDA receptors and fully occupies this site at some functional synapses.
1,079 citations
TL;DR: The degree of astrocytic coverage of neurons governs the level of glycine site occupancy on the NMDA receptor, thereby affecting their availability for activation and thus the activity dependence of long-term synaptic changes.
836 citations
TL;DR: The demonstration of interrelationships between neural mechanisms underlying hyperalgesia and morphine tolerance may lead to a better understanding of the neurobiology of these two phenomena in particular and pain in general and provide a scientific basis for improved pain management with opiate analgesics.
Abstract: Over the last several years, compelling evidence has accumulated indicating that central hyperactive states resulting from neuronal plastic changes within the spinal cord play a critical role in hyperalgesia associated with nerve injury and inflammation. Such neuronal plastic changes may involve activation of central nervous system excitatory amino acid (EAA) receptors, subsequent intracellular cascades including protein kinase C translocation and activation as well as nitric oxide production, leading to the functional modulation of receptor-ion channel complexes. Similar EAA receptor-mediated cellular and intracellular mechanisms have now been implicated in the development of tolerance to the analgesic effects of morphine, and a site of action involved in both hyperalgesia and morphine tolerance is likely to be in the superficial laminae of the spinal cord dorsal horn. These observations suggest that hyperalgesia and morphine tolerance, two seemingly unrelated phenomena, may be interrelated by common neural substrates that interact at the level of EAA receptor activation and related intracellular events. This view is supported by recent observations showing that thermal hyperalgesia develops when animals are made tolerant to morphine antinociception and that both hyperalgesia and reduction of the antinociceptive effects of morphine occur as a consequence of peripheral nerve injury. The demonstration of interrelationships between neural mechanisms underlying hyperalgesia and morphine tolerance may lead to a better understanding of the neurobiology of these two phenomena in particular and pain in general. This knowledge may also provide a scientific basis for improved pain management with opiate analgesics.
834 citations