Discovery of Prostamide F2α and Its Role in Inflammatory Pain and Dorsal Horn Nociceptive Neuron Hyperexcitability

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.

Identification of prostamides, fatty acyl ethanolamines, and their biosynthetic precursors in rabbit cornea

“…PGF 2 ␣ -EA is involved in infl ammatory pain and dorsal horn nociceptive neuron excitability, while PGE 2 -EA increases blood fl ow and reduces mean arterial pressure in the renal medulla, exhibits strong neuroprotective properties in cerebellar neurons, and along with PGD 2 -EA, induces apoptosis in an in vitro model of colorectal carcinoma (18)(19)(20)(21). Prostamides do not show potent interaction with prostanoid receptors, and studies using isolated feline iris cells have suggested the presence of prostamide-sensitive receptors different from the ones responding to PGs (22)(23)(24).…”

Endocannabinoid system and pain: an introduction

“…Artificially elevating EC levels can unmask alternative metabolic routes, producing additional bioactive products. Interestingly, pathological conditions such as chronic pain states are associated with changes in levels of enzymes, such as cyclooxygenase (COX), lipoxygenase, αβ hydrolase and members of the cytochrome P450 family (122)(123)(124)(125) , which can metabolise the EC to novel lipid signalling molecules. The physiological actions of these metabolic products are as yet unknown, but some preliminary investigations have been performed.…”

Recent Progress in Prostaglandin F2αEthanolamide (Prostamide F2α) Research and Therapeutics

“…It also reduced adipogenic responses to bimatoprost (Silvestri et al, 2013). In a study involving prostamide F 2a , as opposed to bimatoprost, AGN 211336 reduced the nociceptive neuronal firing and behavioral response to spinal application of prostamide F 2a (Gatta et al, 2012). Finally, a very close congener AGN 211335, provided invaluable pharmacological support for those studies intended to clone the prostamide receptor .…”

“…The discovery of prostamide/PGF synthase and its distribution (Moriuchi et al, 2008) was not only instrumental in defining prostamide F 2a as an endogenous prostamide (Gatta et al, 2012), it also provided direction for further investigation of biologic roles. In adult mice, prostamide/PGF synthase was found to be widely expressed in the brain, predominantly in the white matter (Yoshikawa et al, 2011).…”