Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

An endocannabinoid mechanism for stress-induced analgesia

Nature volume 435, pages 1108–1112 (2005)Cite this article

Abstract

Acute stress suppresses pain by activating brain pathways that engage opioid or non-opioid mechanisms. Here we show that an opioid-independent form of this phenomenon, termed stress-induced analgesia1, is mediated by the release of endogenous marijuana-like (cannabinoid) compounds in the brain. Blockade of cannabinoid CB1 receptors in the periaqueductal grey matter of the midbrain prevents non-opioid stress-induced analgesia. In this region, stress elicits the rapid formation of two endogenous cannabinoids, the lipids 2-arachidonoylglycerol2 (2-AG) and anandamide3. A newly developed inhibitor of the 2-AG-deactivating enzyme, monoacylglycerol lipase4,5, selectively increases 2-AG concentrations and, when injected into the periaqueductal grey matter, enhances stress-induced analgesia in a CB1-dependent manner. Inhibitors of the anandamide-deactivating enzyme fatty-acid amide hydrolase6, which selectively elevate anandamide concentrations, exert similar effects. Our results indicate that the coordinated release of 2-AG and anandamide in the periaqueductal grey matter might mediate opioid-independent stress-induced analgesia. These studies also identify monoacylglycerol lipase as a previously unrecognized therapeutic target.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: CB 1 receptors mediate non-opioid stress-induced analgesia.
Figure 2: Stress stimulates the formation of 2-AG and anandamide in dorsal midbrain.
Figure 3: URB602 is a selective MGL inhibitor.
Figure 4: The MGL inhibitor URB602 enhances non-opioid stress-induced analgesia.
Figure 5: Inhibitors of anandamide hydrolysis (URB597) and transport (VDM11) enhance non-opioid stress-induced analgesia.

Similar content being viewed by others

References

  1. Lewis, J. W., Cannon, J. T. & Liebeskind, J. C. Opioid and nonopioid mechanisms of stress analgesia. Science 208, 623–625 (1980)

    Article  ADS  CAS  Google Scholar 

  2. Mechoulam, R. et al. Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. Biochem. Pharmacol. 50, 83–90 (1995)

    Article  CAS  Google Scholar 

  3. Devane, W. A. et al. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science 258, 1946–1949 (1992)

    Article  ADS  CAS  Google Scholar 

  4. Dinh, T. P. et al. Brain monoglyceride lipase participating in endocannabinoid inactivation. Proc. Natl Acad. Sci. USA 99, 10819–10824 (2002)

    Article  ADS  CAS  Google Scholar 

  5. Dinh, T. P., Kathuria, S. & Piomelli, D. RNA interference suggests a primary role for monoacylglycerol lipase in the degradation of the endocannabinoid 2-arachidonoylglycerol. Mol. Pharmacol. 66, 1260–1264 (2004)

    Article  CAS  Google Scholar 

  6. Cravatt, B. F. et al. Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides. Nature 384, 83–87 (1996)

    Article  ADS  CAS  Google Scholar 

  7. Walker, J. M. & Hohmann, A. G. in Cannabinoids—Handbook of Experimental Pharmacology (ed. Pertwee, R.) 509–554 (Springer, Berlin, 2005)

    Google Scholar 

  8. Akil, H., Young, E., Walker, J. M. & Watson, S. J. The many possible roles of opioids and related peptides in stress-induced analgesia. Ann. NY Acad. Sci. 467, 140–153 (1986)

    Article  ADS  CAS  Google Scholar 

  9. Herkenham, M. et al. Characterization and localization of cannabinoid receptors in rat brain: a quantitative in vitro autoradiographic study. J. Neurosci. 11, 563–583 (1991)

    Article  CAS  Google Scholar 

  10. Zimmer, A., Zimmer, A. M., Hohmann, A. G., Herkenham, M. & Bonner, T. I. Increased mortality, hypoactivity, and hypoalgesia in cannabinoid CB1 receptor knockout mice. Proc. Natl Acad. Sci. USA 96, 5780–5785 (1999)

    Article  ADS  CAS  Google Scholar 

  11. Hohmann, A. G., Martin, W. J., Tsou, K. & Walker, J. M. Inhibition of noxious stimulus-evoked activity of spinal cord dorsal horn neurons by the cannabinoid WIN 55,212–2. Life Sci. 56, 2111–2118 (1995)

    Article  CAS  Google Scholar 

  12. Hohmann, A. G., Tsou, K. & Walker, J. M. Cannabinoid suppression of noxious heat-evoked activity in wide dynamic range neurons in the lumbar dorsal horn of the rat. J. Neurophysiol. 81, 575–583 (1999)

    Article  CAS  Google Scholar 

  13. Martin, W. J., Hohmann, A. G. & Walker, J. M. Suppression of noxious stimulus-evoked activity in the ventral posterolateral nucleus of the thalamus by a cannabinoid agonist: correlation between electrophysiological and antinociceptive effects. J. Neurosci. 16, 6601–6611 (1996)

    Article  CAS  Google Scholar 

  14. Meng, I. D., Manning, B. H., Martin, W. J. & Fields, H. L. An analgesia circuit activated by cannabinoids. Nature 395, 381–383 (1998)

    Article  ADS  CAS  Google Scholar 

  15. Calignano, A., La Rana, G., Giuffrida, A. & Piomelli, D. Control of pain initiation by endogenous cannabinoids. Nature 394, 277–281 (1998)

    Article  ADS  CAS  Google Scholar 

  16. Terman, G. W., Lewis, J. W. & Liebeskind, J. C. Two opioid forms of stress analgesia: studies of tolerance and cross-tolerance. Brain Res. 368, 101–106 (1986)

    Article  CAS  Google Scholar 

  17. Walker, J. M., Huang, S. M., Strangman, N. M., Tsou, K. & Sañudo-Peña, M. C. Pain modulation by release of the endogenous cannabinoid anandamide. Proc. Natl Acad. Sci. USA 96, 12198–12203 (1999)

    Article  ADS  CAS  Google Scholar 

  18. Martin, W. J., Patrick, S. L., Coffin, P. O., Tsou, K. & Walker, J. M. An examination of the central sites of action of cannabinoid-induced antinociception in the rat. Life Sci. 56, 2103–2109 (1995)

    Article  CAS  Google Scholar 

  19. Cannon, J. T., Prieto, G. J., Lee, A. & Liebeskind, J. C. Evidence for opioid and non-opioid forms of stimulation-produced analgesia in the rat. Brain Res. 243, 315–321 (1982)

    Article  CAS  Google Scholar 

  20. Tsou, K., Brown, S., Sañudo-Peña, M. C., Mackie, K. & Walker, J. M. Immunohistochemical distribution of cannabinoid CB1 receptors in the rat central nervous system. Neuroscience 83, 393–411 (1998)

    Article  CAS  Google Scholar 

  21. Kathuria, S. et al. Modulation of anxiety through blockade of anandamide hydrolysis. Nature Med. 1, 76–81 (2003)

    Article  Google Scholar 

  22. Mor, M. et al. Cyclohexylcarbamic acid 3′- or 4′-substituted biphenyl-3-yl esters as fatty acid amide hydrolase inhibitors: synthesis, quantitative structure–activity relationships, and molecular modeling studies. J. Med. Chem. 47, 4998–5008 (2004)

    Article  CAS  Google Scholar 

  23. Stella, N., Schweitzer, P. & Piomelli, D. A second endogenous cannabinoid that modulates long-term potentiation. Nature 388, 773–778 (1997)

    Article  ADS  CAS  Google Scholar 

  24. Kozak, K. R., Prusakiewicz, J. J. & Marnett, L. J. Oxidative metabolism of endocannabinoids by COX-2. Curr. Pharm. Des. 10, 659–667 (2004)

    Article  CAS  Google Scholar 

  25. De Petrocellis, L., Bisogno, T., Davis, J. B., Pertwee, R. G. & Di Marzo, V. Overlap between the ligand recognition properties of the anandamide transporter and the VR1 vanilloid receptor: inhibitors of anandamide uptake with negligible capsaicin-like activity. FEBS Lett. 483, 52–56 (2000)

    Article  CAS  Google Scholar 

  26. Vaughan, C. W., Connor, M., Bagley, E. E. & Christie, M. J. Actions of cannabinoids on membrane properties and synaptic transmission in rat periaqueductal gray neurons in vitro. Mol. Pharmacol. 57, 288–295 (2000)

    CAS  PubMed  Google Scholar 

  27. Valverde, O., Ledent, C., Beslot, F., Parmentier, M. & Roques, B. P. Reduction of stress-induced analgesia but not of exogenous opioid effects in mice lacking CB1 receptors. Eur. J. Neurosci. 12, 533–539 (2000)

    Article  CAS  Google Scholar 

  28. Piomelli, D. The molecular logic of endocannabinoid signalling. Nature Rev. Neurosci. 4, 873–884 (2003)

    Article  MathSciNet  CAS  Google Scholar 

  29. Tarzia, G. et al. Design, synthesis, and structure–activity relationships of alkylcarbamic acid aryl esters, a new class of fatty acid amide hydrolase inhibitors. J. Med. Chem. 46, 2352–2360 (2003)

    Article  CAS  Google Scholar 

  30. Giuffrida, A., Rodríguez de Fonseca, F. & Piomelli, D. Quantification of bioactive acylethanolamides in rat plasma by electrospray mass spectrometry. Anal. Biochem. 280, 87–93 (2000)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The assistance of the Centro di Calcolo at the University of Parma is gratefully acknowledged. This research was supported by grants from the National Institute on Drug Abuse (A.G.H., D.P.) and from the MIUR and the Universities of Parma and Urbino ‘Carlo Bo’.

Author information

Authors and Affiliations

  1. Neuroscience and Behavior Program, Department of Psychology, The University of Georgia, Athens, Georgia, 30602-3013, USA

    Andrea G. Hohmann, Richard L. Suplita, Nathan M. Bolton, Mark H. Neely, Philip V. Holmes & Jonathon D. Crystal

  2. Department of Pharmacology and Center for Drug Discovery, University of California, Irvine, California, 92697-4260, USA

    Darren Fegley, Regina Mangieri & Daniele Piomelli

  3. Schrier Research Laboratory, Departments of Psychology and Neuroscience, Brown University, Rhode, Providence, Island, 02912, USA

    Jocelyn F. Krey & J. Michael Walker

  4. Institute of Medicinal Chemistry, University of Urbino Carlo Bo, I-61029, Urbino, Italy

    Andrea Duranti, Andrea Tontini & Giorgio Tarzia

  5. Pharmaceutical Department, University of Parma, I-43100, Parma, Italy

    Marco Mor

Authors
  1. Andrea G. Hohmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Richard L. Suplita
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Nathan M. Bolton
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mark H. Neely
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Darren Fegley
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Regina Mangieri
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jocelyn F. Krey
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. J. Michael Walker
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Philip V. Holmes
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Jonathon D. Crystal
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Andrea Duranti
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Andrea Tontini
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Marco Mor
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Giorgio Tarzia
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Daniele Piomelli
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Andrea G. Hohmann or Daniele Piomelli.

Ethics declarations

Competing interests

A patent has been filed on their behalf by the University of California at Irvine.

Supplementary information

Supplementary Figure S1

Systemic administration of the CB1 antagonist AM251 suppresses non-opioid stress-induced antinociception. (PDF 9 kb)

Supplementary Figure S2

Rimonabant does not alter tail-flick latencies in the absence of the stressor. (PDF 8 kb)

Supplementary Figure S3

Non-opioid stress-induced antinociception is unaffected by morphine tolerance. (PDF 7 kb)

Supplementary Figure S4

Rimonabant does not alter stress-induced antinociception following microinjection in the lateral/ventrolateral PAG. (PDF 29 kb)

Supplementary Figure S5

Administration of rimonabant into the lateral ventricle does not affect opioid-independent stress-induced antinociception. (PDF 10 kb)

Supplementary Figure S6

Representative LC/MS tracings for selected ions characteristic of endogenous 2-AG, synthetic [2H8]-2-AG standard, endogenous anandamide and synthetic [2H4]-2-anandamide standard. (PDF 33 kb)

Supplementary Figure S7

Coronal reconstructions of injection sites following microinjection of URB602 in the (a) dorsolateral or (b,c) lateral/ventrolateral PAG. (PDF 80 kb)

Supplementary Figure S8

Coronal reconstructions of injection sites following microinjection of URB597 in the dorsolateral PAG. (PDF 41 kb)

Supplementary Figure S9

Inhibition of MGL enhances nonopioid stress-induced analgesia. (PDF 54 kb)

Supplementary Figure S1 Legend (DOC 22 kb)

Supplementary Figure S2 Legend (DOC 21 kb)

Supplementary Figure S3 Legend (DOC 22 kb)

Supplementary Figure S4 Legend (DOC 22 kb)

Supplementary Figure S5 Legend (DOC 21 kb)

Supplementary Figure S6 Legend (DOC 24 kb)

Supplementary Figure S7 Legend (DOC 22 kb)

Supplementary Figure S8 Legend (DOC 21 kb)

Supplementary Figure S9 Legend (DOC 25 kb)

Supplementary Methods (DOC 31 kb)

Supplementary Table (DOC 32 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hohmann, A., Suplita, R., Bolton, N. et al. An endocannabinoid mechanism for stress-induced analgesia. Nature 435, 1108–1112 (2005). https://doi.org/10.1038/nature03658

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature03658

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing