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Control of pain initiation by endogenous cannabinoids


The potent analgesic effects of cannabis-like drugs1,2,3,4 and the presence of CB1-type cannabinoid receptors in pain-processing areas of the brain and spinal cord5,6 indicate that endogenous cannabinoids such as anandamide7 may contribute to the control of pain transmission within the central nervous system (CNS)8. Here we show that anandamide attenuates the pain behaviour produced by chemical damage to cutaneous tissue by interacting with CB1-like cannabinoid receptors located outside the CNS. Palmitylethanolamide (PEA), which is released together with anandamide from a common phospholipid precursor9, exerts a similar effect by activating peripheral CB2-like receptors. When administered together, the two compounds act synergistically, reducing pain responses 100-fold more potently than does each compound alone. Gas-chromatography/mass-spectrometry measurements indicate that the levels of anandamide and PEA in the skin are enough to cause a tonic activation of local cannabinoid receptors. In agreement with this possibility, the CB1 antagonist SR141716A and the CB2 antagonist SR144528 prolong and enhance the pain behaviour produced by tissue damage. These results indicate that peripheral CB1-like and CB2-like receptors participate in the intrinsic control of pain initiation and that locally generated anandamide and PEA may mediate this effect.

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Figure 1: Anandamide inhibits formalin-evoked nociception by activating peripheral CB1-like cannabinoid receptors.
Figure 2: PEA inhibits formalin-evoked nociception by activating peripheral CB2-like cannabinoid receptors.
Figure 3: Anandamide and PEA synergistically inhibit formalin-evoked nociception.
Figure 4: Intrinsic hyperalgesic effects of cannabinoid antagonists on the time course of formalin-evoked nociception.
Figure 5: Identification by gas chromatography/mass spectrometry of anandamide and PEA in rat paw skin.


  1. Martin, B. R., Balster, R. L., Razdan, R. K., Harris, L. S. & Dewey, W. L. Behavioral comparisons of the stereoisomers of tetrahydrocannabinols. Life Sci. 20, 565–574 (1981).

    Article  Google Scholar 

  2. Martin, W. J., Lai, N. K., Patrick, S. L., Tsou, K. & Walker, J. M. Antinociceptive actions of cannabinoids following intraventricular administration in rats. Brain Res. 629, 300–304 (1993).

    CAS  Article  Google Scholar 

  3. Tsou, K. et al. Suppression of noxious stimulus-evoked expression of FOS protein-like immunoreactivity in rat spinal cord by a selective cannabinoid agonist. Neuroscience 70, 791–798 (1996).

    CAS  Article  Google Scholar 

  4. Lichtman, A. H., Cook, S. A. & Martin, B. R. Investigation of brain sites mediating cannabinoid-induced antinociception in rats: evidence supporting periaqueductal gray involvement. J. Pharmacol. Exp. Ther. 276, 585–593 (1996).

    CAS  PubMed  Google Scholar 

  5. Herkenham, M. et al. Cannabinoid receptor localization in brain. Proc. Natl Acad. Sci. USA 87, 1932–1936 (1990).

    ADS  CAS  Article  Google Scholar 

  6. 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).

    CAS  Article  Google Scholar 

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

    ADS  CAS  Article  Google Scholar 

  8. Richardson, J. D., Aanonsen, L. & Hargreaves, K. M. Hypoactivity of the spinal cannabinoid system results in NMDA-dependent hyperalgesia. J. Neurosci. 18, 451–457 (1998).

    CAS  Article  Google Scholar 

  9. Di Marzo, V. et al. Formation and inactivation of endogenous cannabinoid anandamide in central neurons. Nature 372, 686–691 (1994).

    ADS  CAS  Article  Google Scholar 

  10. Fields, H. L. Pain(McGraw-Hill, New York, (1987)).

    Google Scholar 

  11. Stein, C. The control of pain in peripheral tissue by opioids. New Engl. J. Med. 332, 1685–1690 (1995).

    CAS  Article  Google Scholar 

  12. Dubuisson, D. & Dennis, S. G. The formalin test: a quantitative study of the analgesic effects of morphine, meperidine, and brain stem stimulation in rats and cats. Pain 4, 161–174 (1977).

    CAS  Article  Google Scholar 

  13. Dickenson, A. H. & Sullivan, A. F. Subcutaneous formalin-induced activity of dorsal horn neurones in the rat: differential response to an intrathecal opiate administered pre or post formalin. Pain 30, 349–360 (1987).

    CAS  Article  Google Scholar 

  14. Rosland, J. H., Tjølsen, A., Maehle, B. & Hole, K. The formalin test in mice: effect of formalin concentration. Pain 42, 235–242 (1990).

    CAS  Article  Google Scholar 

  15. Coderre, T. J. & Melzack, R. The contribution of excitatory amino acids to central sensitization and persistent nociception after formalin-induced tissue injury. J. Neurosci. 12, 3665–3670 (1992).

    CAS  Article  Google Scholar 

  16. Rinaldi-Carmona, M. et al. SR 144528, the first potent and selective antagonist of the CB2 cannabinoid receptor. J. Pharmacol. Exp. Ther. 284, 644–650 (1998).

    CAS  PubMed  Google Scholar 

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

    ADS  CAS  Article  Google Scholar 

  18. Beltramo, M. et al. Functional role of high-affinity anandamide transport, as revealed by selective inhibition. Science 277, 1094–1097 (1997).

    CAS  Article  Google Scholar 

  19. Cadas, H., di Tomaso, E. & Piomelli, D. Occurrence and biosynthesis of endogenous cannabinoid precursor, N-arachidonoyl phosphatidylethanolamine, in rat brain. J. Neurosci. 17, 1226–1242 (1997).

    CAS  Article  Google Scholar 

  20. Schmid, H. H. O., Schmid, P. C. & Natarajan, V. The N-acylation-phosphodiesterase pathway and cell signalling. Chem. Phys. Lipids 80, 133–142 (1996).

    CAS  Article  Google Scholar 

  21. Aloe, L., Leon, A. & Levi-Montalcini, R. Aproposed autacoid mechanism controlling mastocyte behaviour. Agents Actions 39, C145–C147 (1993).

    CAS  Article  Google Scholar 

  22. Mazzari, S., Canella, R., Petrelli, L., Marcolongo, G. & Leon, A. N-(2-hydroxyethyl)hexadecanamide is orally active in reducing edema formation and inflammatory hyperalgesia by down-modulating mast cell activation. Eur. J. Pharmacol. 300, 227–236 (1996).

    CAS  Article  Google Scholar 

  23. Facci, L. et al. Mast cells express a peripheral cannabinoid receptor with differential sensitivity to anandamide and palmitoylethanolamide. Proc. Natl Acad. Sci. USA 92, 3376–3380 (1995).

    ADS  CAS  Article  Google Scholar 

  24. Showalter, V. M., Compton, D. R., Martin, B. R. & Abood, M. E. Evaluation of binding in a transfected cell line expressing a peripheral cannabinoid receptor (CB2): identification of cannabinoid receptor subtype selective ligands. J. Pharmacol. Exp. Ther. 278, 989–999 (1996).

    CAS  PubMed  Google Scholar 

  25. Munro, S., Thomas, K. L. & Abu-Shaar, M. Molecular characterization of a peripheral receptor for cannabinoids. Nature 365, 61–65 (1993).

    ADS  CAS  Article  Google Scholar 

  26. Landsman, R. S., Burkey, T. H., Consroe, P., Roeske, W. R. & Yamamura, H. I. SR141716A is an inverse agonist at the human cannabinoid CB1 receptor. Eur. J. Pharmacol. 334, R1–R2 (1997).

    CAS  Article  Google Scholar 

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

    ADS  CAS  Article  Google Scholar 

  28. Giuffrida, A. & Piomelli, D. Isotope dilution GC/MS determination of anandamide and other fatty acylethanolamides in rat blood plasma. FEBS Lett. 422, 373–376 (1998).

    CAS  Article  Google Scholar 

  29. Jaggar, S. I., Hasnie, F. S., Sellatwray, S. & Rice, A. S. C. The antihyperalgesic actions of the cannabinoid anandamide and the putative CB2 receptor agonist palmitoylethanolamide in visceral and somatic inflammatory pain. Pain(in the press).

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We thank P. Cimminiello, F. De Seta and V. Piscicelli for experimental assistance, and M. Beltramo, A. Makriyannis, L. Sorrentino and N. Stella for discussion. Supported by Neurosciences Research Foundation (A.G. and D.P.), which receives major support from Novartis, and by MURST (G.L.R. and A.C.).

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Correspondence to Daniele Piomelli.

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Calignano, A., Rana, G., Giuffrida, A. et al. Control of pain initiation by endogenous cannabinoids. Nature 394, 277–281 (1998).

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