Control of pain initiation by endogenous cannabinoids

The potent analgesic effects of cannabis-like drugs and the presence of CBl-type receptors in pain-processing areas of the brain and spinal cord indicated that endogenous cannabinoids such as anandamide may contribute to the control of pain transmission within the central nervous system (CNS). Here we show that anandamide attenuates the pain behavior produced by chemical damage to cutaneous tissue by interacting with CBl-like cannabinoid receptors located outside the CNS. Palmitylethanolamide (PEA), which is released together with anandamide from a common phospholipid precursor, exerts a similar effect by activating peripheral CB2-like receptors. When administered together, the two compounds act synergistically, reducing the 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 SR121716A and the CB2 antagonist SR144528 prolong and enhance pain behavior produced by tissue damage. These results indicate that peripheral CBl-like and CB2-like receptors participate in the intrinsic control of pain initiation and that locally generated anandamide and PEA may mediate this effect.