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How opioids inhibit GABA-mediated neurotransmission

Nature volume 390, pages 611–614 (1997)Cite this article

Abstract

The midbrain region periaqueductal grey (PAG) is rich in opioid receptors and endogenous opioids and is a major target of analgesic action in the central nervous system1. It has been proposed that the analgesic effect of opioids on the PAG works by suppressing the inhibitory influence of the neurotransmitter GABA (γ-aminobutyric acid) on neurons that form part of a descending antinociceptive pathway2. Opioids inhibit GABA-mediated (GABAergic) synaptic transmission in the PAG and other brain regions by reducing the probability of presynaptic neurotransmitter release3,4, but the mechanisms involved remain uncertain. Here we report that opioid inhibition of GABAergic synaptic currents in the PAG is controlled by a presynaptic voltage-dependent potassium conductance. Opioid receptors of the μ type in GABAergic presynaptic terminals are specifically coupled to this potassium conductance by a pathway involving phospholipase A2, arachidonic acid and 12-lipoxygenase. Furthermore, opioid inhibition of GABAergic synaptic transmission is potentiated by inhibitors of the enzymes cyclooxygenase and 5-lipoxygenase, presumably because more arachidonic acid is available for conversion to 12-lipoxygenase products. These mechanisms account for the analgesic action of cyclooxygenase inhibitors in the PAG5 and their synergism with opioids6.

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Figure 1: Effect of K+ conductance blockade on GABAergic synaptic transmission.
Figure 3: Potentiation of opioid inhibition of GABAergic synaptic transmission by cyclooxygenase and 5-lipoxygenase blockade.
Figure 2: Effect of second messenger modulation on GABAergic synaptic transmission.

References

  1. Mansour, A., Fox, C. A., Akil, H. & Watson, S. J. Opioid-receptor mRNA expression in the rat CNS — anatomical and functional implications. Trends Neurosci. 18, 22–29 (1995).

    Article  CAS  Google Scholar 

  2. Basbaum, A. I. & Fields, H. L. Endogenous pain control systems: brainstem spinal pathways and endorphin circuitry. Annu. Rev. Neurosci. 7, 309–338 (1984).

    Article  CAS  Google Scholar 

  3. Capogna, M., Gahwiler, B. H. & Thompson, S. M. Mechanism of μ-opioid receptor-mediated presynaptic inhibition in the rat hippocampus in vitro. J. Physiol. (Lond.) 470, 539–558 (1993).

    Article  CAS  Google Scholar 

  4. Vaughan, C. W. & Christie, M. J. Presynaptic inhibitory action of opioids on synaptic transmission in the rat periaqueductal grey in vitro. J. Physiol. (Lond.) 498, 463–472 (1997).

    Article  CAS  Google Scholar 

  5. Tortorici, V. & Vanegus, H. Anti-nociception induced by systemic or PAG-microinjected lysine–acetylsalicylate in rats. Effects on tail-flick related activity of medullary off- and on-cells. Eur. J. Neurosci. 7, 1857–1865 (1995).

    Article  CAS  Google Scholar 

  6. Maves, T. J., Pechman, P. S., Meller, S. T. & Gebhart, G. F. Ketorolac potentiates morphine antinociception during visceral nociception in the rat. Anesthesiology 80, 1094–1101 (1994).

    Article  CAS  Google Scholar 

  7. North, R. A. Opioid actions on membrane ion channels.in Opioids (ed. Herz, A.) 773–798 (Springer, Berlin, (1993)).

  8. Wimpey, T. & Chavkin, C. Opioids activate both an inward rectifier and a novel voltage-gated potassium conductance in the hippocampal formation. Neuron 6, 281–289 (1991).

    Article  CAS  Google Scholar 

  9. Grissmer, S. et al. Pharmacological characterization of five cloned voltage gated K+ channels, types Kv1.1, 1.2, 1.3, 1.5, and 3.1, stably expressed in mammalian cell lines. Mol. Pharmacol. 45, 1227–1234 (1994).

    CAS  PubMed  Google Scholar 

  10. Vaughan, C. W., Ingram, S. L. & Christie, M. J. Actions of the ORL1receptor ligand, nociceptin, on membrane properties of rat periaqueductal gray neurons in vitro. J. Neurosci. 17, 996–1003 (1997).

    Article  CAS  Google Scholar 

  11. Simmons, M. L. & Chavkin, C. κ-Opioid receptor activation of a dendrotoxin-sensitive potassium channel mediates presynaptic inhibition of mossy fiber neurotransmitter release. Mol. Pharmacol. 50, 80–85 (1996).

    CAS  PubMed  Google Scholar 

  12. Shapiro, M., Wollmuth, L. & Hille, B. Modulation of Ca2+ channels by PTX-sensitive G-proteins is blocked by N-ethylmaleimide in rat sympathetic neurons. J. Neurosci. 14, 7109–7116 (1994).

    Article  CAS  Google Scholar 

  13. Capogna, M., Gahwiler, B. H. & Thompson, S. M. Presynaptic enhancement of inhibitory synaptic transmission in the rat hippocampus in vitro. J. Neurosci. 15, 1249–1260 (1995).

    Article  CAS  Google Scholar 

  14. Fukuda, K., Kato, S., Morikawa, H., Shoda, T. & Mori, K. Functional coupling of the δ-, μ-, and κ-opioid receptors to mitogen-activated protein kinase and arachidonate release in chinese hamster ovary cells. J. Neurochem. 67, 1309–1316 (1996).

    Article  CAS  Google Scholar 

  15. Blackwell, G. J. & Flower, R. J. Inhibition of phospholipase. Brit. Med. Bull. 39, 260–264 (1983).

    Article  CAS  Google Scholar 

  16. Piomelli, D. & Greengard, P. Lipoxygenase metabolites of arachidonic acid in neuronal transmembrane signalling. Trends Pharmacol. Sci. 11, 367–373 (1990).

    Article  CAS  Google Scholar 

  17. Duerson, K., White, R. E., Jiang, F., Schonbrunn, A. & Armstrong, D. L. Somatostatin stimulates BKCa channels in rat pituitary tumor cells through lipoxygenase metabolites of arachidonic acid. Neuropharmacology 35, 949–961 (1996).

    Article  CAS  Google Scholar 

  18. Shimizu, T. & Wolfe, L. S. Arachidonic acid cascade and signal transduction. J. Neurochem. 55, 1–15 (1990).

    Article  CAS  Google Scholar 

  19. Evans, J. F. et al. 5-Lipoxygenase-activating protein is the target of a quinole class of leukotriene synthesis inhibitors. Mol. Pharmacol. 40, 22–27 (1991).

    CAS  PubMed  Google Scholar 

  20. Kurachi, Y. et al. α-Adrenergic activation of the muscarinic K+ channel is mediated by arachidonic acid metabolites. Pflugers Arch. 414, 102–104 (1989).

    Article  CAS  Google Scholar 

  21. Schweitzer, P., Madamba, S. & Siggins, G. R. Arachidonic acid metabolites as mediators of somatostatin-induced increase of neuronal M-current. Nature 346, 464–467 (1990).

    Article  ADS  CAS  Google Scholar 

  22. Piomelli, D. et al. Lipoxygenase metabolites of arachidonic acid as second messengers for presynaptic inhibition of Aplysia sensory cells. Nature 328, 38–43 (1987).

    Article  ADS  CAS  Google Scholar 

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Acknowledgements

We thank J. P. Seale for reading the manuscript and K. Earle for help with the analysis. This work was supported by the NH and MRC of Australia and Human Frontiers in Science Program (S.L.I.).

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Authors and Affiliations

  1. Department of Pharmacology, The University of Sydney, Sydney, 2006, New South Wales, Australia

    C. W. Vaughan, S. L. Ingram, M. A. Connor & M. J. Christie

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  1. C. W. Vaughan
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  2. S. L. Ingram
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Correspondence to C. W. Vaughan.

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Vaughan, C., Ingram, S., Connor, M. et al. How opioids inhibit GABA-mediated neurotransmission. Nature 390, 611–614 (1997). https://doi.org/10.1038/37610

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