Abstract
It was suggested that endocannabinoids are metabolized by cyclooxygenase (COX)-2 in the spinal cord of rats with kaolin/λ-carrageenan-induced knee inflammation, and that this mechanism contributes to the analgesic effects of COX-2 inhibitors in this experimental model. We report the development of a specific method for the identification of endocannabinoid COX-2 metabolites, its application to measure the levels of these compounds in tissues, and the finding of prostamide F2α (PMF2α) in mice with knee inflammation. Whereas the levels of spinal endocannabinoids were not significantly altered by kaolin/λ-carrageenan-induced knee inflammation, those of the COX-2 metabolite of AEA, PMF2α, were strongly elevated. The formation of PMF2α was reduced by indomethacin (a non-selective COX inhibitor), NS-398 (a selective COX-2 inhibitor) and SC-560 (a selective COX-1 inhibitor). In healthy mice, spinal application of PMF2α increased the firing of nociceptive (NS) neurons, and correspondingly reduced the threshold of paw withdrawal latency (PWL). These effects were attenuated by the PMF2α receptor antagonist AGN211336, but not by the FP receptor antagonist AL8810. Also prostaglandin F2α increased NS neuron firing and reduced the threshold of PWL in healthy mice, and these effects were antagonized by AL8810, and not by AGN211336. In mice with kaolin/λ-carrageenan-induced knee inflammation, AGN211336, but not AL8810, reduced the inflammation-induced NS neuron firing and reduction of PWL. These findings suggest that inflammation-induced, and prostanoid-mediated, enhancement of dorsal horn NS neuron firing stimulates the production of spinal PMF2α, which in turn contributes to further NS neuron firing and pain transmission by activating specific receptors.
Highlights
Activation of cannabinoid receptors of type-1 (CB1) and/or -2 (CB2) by synthetic agonists as well as by the two most studied endocannabinoids, anandamide (AEA) and 2-arachidonoylglycerol (2-AG), has been proposed as a novel anti-hyperalgesic strategy based on studies carried out in several experimental models of inflammatory and neuropathic pain [1,2]
In view of these considerations, and of the increasingly accepted role of COX-2 in the inactivation of endocannabinoids in both spinal [14] and supra-spinal [15,16] structures, we have investigated here whether COX-2 metabolites of AEA and 2-AG, known as prostaglandin-ethanolamides and prostaglandin-glycerol esters (PG-GEs) are formed in the spinal cord of mice with knee inflammation, and if they play any role in NS neuron hyperexcitability and hyperalgesia
The present study was aimed at evaluating the hypothesis that knee inflammation causes production of COX-2 metabolites of endocannabinoids in the spinal cord
Summary
Activation of cannabinoid receptors of type-1 (CB1) and/or -2 (CB2) by synthetic agonists as well as by the two most studied endocannabinoids, anandamide (AEA) and 2-arachidonoylglycerol (2-AG), has been proposed as a novel anti-hyperalgesic strategy based on studies carried out in several experimental models of inflammatory and neuropathic pain [1,2]. If during knee inflammation, endocannabinoids are substrates for COX-2, inhibition of FAAH alone would not be sufficient to counteract their inactivation, and might even favor the COX-2-catalysed formation of endocannabinoid-derived oxidation products, which might exert pro-inflammatory and pro-algesic effects per se, as suggested previously [8], via specific and yet to be fully identified noncannabinoid, non-prostanoid receptors [9] In support of this possibility, a prostaglandin F synthase isoform with activity on the ‘‘AEA-endoperoxyde’’ derived from COX-2 was recently cloned and identified in myelin sheaths of the mouse brain and spinal cord [10]. The only available data on the formation of AEA COX-2 derivatives in vivo is from studies in which FAAH2/2 mice were treated with exogenous AEA [11], and even evidence in vitro was obtained only in cells treated with either exogenous AEA [12] or, more recently, a non-physiological stimulus such as ionomycin to increase the intracellular levels of AEA [13]
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