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Inhibition of cyclooxygenase-2 potentiates retrograde endocannabinoid effects in hippocampus

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Abstract

In hippocampal pyramidal cells, a rise in Ca2+ releases endocannabinoids that activate the presynaptic cannabinoid receptor (CB1R) and transiently reduce GABAergic transmission—a process called depolarization-induced suppression of inhibition (DSI). The mechanism that limits the duration of endocannabinoid action in intact cells is unknown. Here we show that inhibition of cyclooxygenase-2 (COX-2), not fatty acid amide hydrolase (FAAH), prolongs DSI, suggesting that COX-2 limits endocannabinoid action.

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Figure 1: Efficacy and specificity of the FAAH inhibitor URB-597.
Figure 2: Selective COX-2 inhibitors prolong DSI.

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Change history

  • 11 June 2004

    appended aop PDF with erratum PDF (will be corrected for print issue), and placed footnote in XML at second-to-last paragraph and in Fig 1 legend

Notes

  1. *Note: In the version of this article initially published online, several lines of text were inadvertently left out of the second-to-last paragraph. The corrected paragraph should read, "This is the first report that COX-2 inhibitors can affect endocannabinoid signaling between neurons, hence COX-2 may help regulate endocannabinoid metabolism in cells6. Our observations are consistent with the report that an analgesic effect of a COX inhibitor is blocked by AM251 (ref. 12), suggesting that COX may regulate endocannabinoid release at the systems level in vivo. Without a specific inhibitor for MGL, we cannot exclude a role for MGL in limiting the DSI time course. The location of MGL, the axon terminals4, suggests that it may degrade 2-AG after uptake into the terminals, if 2-AG is released during DSI (for model, see Supplementary Fig. 1 online). If COX-2, which is only found in excitatory hippocampal cells13, degraded endocannabinoid after it was released, nimesulide would cause an accumulation of endocannabinoid in the extracellular space and suppress the baseline IPSC. However, nimesulide itself did not cause a CB1R-dependent suppression of IPSCs (Fig. 2a,f ). When a droplet of 2-AG was applied to nimesulide-treated slices (15-20 min), the IPSC suppression was similar to that in untreated slices (84 ± 1% of pre-2-AG in nimesulide, n = 5 versus 82 ± 2% in untreated, n = 5) (P > 0.1, t-test; data not shown). Perhaps exogenous 2-AG is not transported to COX-2, or COX-2 specifically regulates the endogenous production of 2-AG." In addition, the legend of Figure 1, second line, contained a typographical error. The phrase should read 'IPSC amplitude'. These mistakes have been corrected for the HTML and print versions of the article.

References

  1. Deutsch, D.G. & Chin, S.A. Biochem. Pharmacol. 46, 791–796 (1993).

    Article  CAS  Google Scholar 

  2. Cravatt, B.F. et al. Nature 384, 83–87 (1996).

    Article  CAS  Google Scholar 

  3. Goparaju, S.K., Ueda, N., Taniguchi, K. & Yamamoto, S. Biochem. Pharmacol. 57, 417–423 (1999).

    Article  CAS  Google Scholar 

  4. Dinh, T.P. et al. Proc. Natl. Acad. Sci. USA 99, 10819–10824 (2002).

    Article  CAS  Google Scholar 

  5. Alger, B.E. Prog. Neurobiol. 68, 247–286 (2002).

    Article  CAS  Google Scholar 

  6. Kozak, K.R., Rowlinson, S.W. & Marnett, L.J. J. Biol. Chem. 275, 33744–33749 (2000).

    Article  CAS  Google Scholar 

  7. Yu, M., Ives, D. & Ramesha, C.S. J. Biol. Chem. 272, 21181–21186 (1997).

    Article  CAS  Google Scholar 

  8. Kathuria, S. et al. Nat. Med. 9, 76–81 (2003).

    Article  CAS  Google Scholar 

  9. Lichtman, A.H., Hawkins, E.G., Griffin, G. & Cravatt, B.F. J. Pharmacol. Exp. Ther. 302, 73–79 (2002).

    Article  CAS  Google Scholar 

  10. Chen, C., Magee, J.C. & Bazan, N.G. J. Neurophysiol. 87, 2851–2857 (2002).

    Article  CAS  Google Scholar 

  11. Fowler, C.J., Tiger, G. & Stenstrom, A. J. Pharmacol. Exp. Ther. 283, 729–734 (1997).

    CAS  PubMed  Google Scholar 

  12. Guhring, H. et al. Eur. J. Pharmacol. 454, 153–163 (2002).

    Article  CAS  Google Scholar 

  13. Kaufmann, W.E., Worley, P.F., Pegg, J., Bremer, M. & Isakson, P. Proc. Natl. Acad. Sci. USA 93, 2317–2321 (1996).

    Article  CAS  Google Scholar 

  14. Tsou, K. et al. Neurosci. Lett. 254, 137–140 (1998).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank S. Thompson and A. Keller for comments, and D. Piomelli for URB-597. The work was supported by National Institutes of Health grants RO1 DA14 725 and RO1 NS30219 to B.E.A. This work is contained in J.K.'s Ph.D. thesis.

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Correspondence to Bradley E Alger.

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Supplementary information

Supplementary Fig. 1

Model of endocannabinoid regulation during DSI. (PDF 107 kb)

Supplementary Methods (PDF 11 kb)

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Kim, J., Alger, B. Inhibition of cyclooxygenase-2 potentiates retrograde endocannabinoid effects in hippocampus. Nat Neurosci 7, 697–698 (2004). https://doi.org/10.1038/nn1262

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