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Synthetic cannabinoids produce behavioral analgesia and suppress pain neurotransmission, raising the possibility that endogenous cannabinoids serve naturally to modulate pain. Here, the development of a sensitive method for measuring cannabinoids by atmospheric pressure-chemical ionization mass spectrometry permitted measurement of the release of the endogenous cannabinoid anandamide in the periaqueductal gray (PAG) by in vivo microdialysis in the rat. Electrical stimulation of the dorsal and lateral PAG produced CB1 cannabinoid receptor-mediated analgesia accompanied by a marked increase in the release of anandamide in the PAG, suggesting that endogenous anandamide mediates the behavioral analgesia. Furthermore, pain triggered by subcutaneous injections of the chemical irritant formalin substantially increased the release of anandamide in the PAG. These findings indicate that the endogenous cannabinoid anandamide plays an important role in a cannabinergic pain-suppression system existing within the dorsal and lateral PAG. The existence of a cannabinergic pain-modulatory system may have relevance for the treatment of pain, particularly in instances where opiates are ineffective.analgesia ͉ periaqueductal gray ͉ microdialysis ͉ gas chromatography ͉ mass spectrometry T he components of an elaborate neural system that serves naturally to modulate pain sensitivity have been detailed by Liebeskind and subsequent workers (1, 2). These early studies revealed that electrical stimulation of the periaqueductal gray (PAG) produces analgesia, demonstrating the presence of an analgesia circuit in the brain (1). When elicited from the ventral portion of the PAG, this electrical stimulation-produced analgesia (SPA) is mediated by the release of endogenous opiates (3). However, when elicited from the dorsal or lateral part of the PAG, the analgesic effect of stimulation is mediated by unidentified nonopiate substances (4).Among the prime candidates for these unknown pain modulatory substances are endogenous cannabinoids-compounds similar to the active ingredient in marijuana. Cannabinoids produce analgesia (5) and dampen the spinal and thalamic neuronal responses to noxious stimuli (6, 7). In attempting to understand the neural basis of cannabinoid analgesia, the PAG was a brain region of interest because of its established role in pain-modulation (8) and the presence of the necessary biological machinery for cannabinoid action (9-12). Like opiates, cannabinoids produce analgesia when microinjected in the PAG (13). However, the anatomical subregions of the PAG that support cannabinoid analgesia were the inverse of those supporting morphine analgesia and opiate-mediated SPA (4, 13, 14): cannabinoids were effective in the dorsal and lateral but not the ventral PAG. These findings led us to speculate that endogenous cannabinoids in the dorsal and lateral PAG may be an important component of the nonopiate analgesia system identified earlier. Herein, we show that electrical stimulation of the dorsal and lateral PAG and the dorsal ad...

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