Control of pain initiation by endogenous cannabinoids

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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.


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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) doi:10.1038/28393

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