Spinal phospholipase A2 in inflammatory hyperalgesia: Role of the small, secretory phospholipase A2
Neuroscience(2005)
Abstract
Current work emphasizes that peripheral tissue injury and inflammation results in a heightened sensitivity to subsequent noxious input (hyperalgesia) that is mediated in large part by the spinal synthesis and release of eicosanoids, in particular prostaglandins. Secreted phospholipase A2s (sPLA2s) form a class of structurally related enzymes that release arachidonic acid from cell membranes that is further processed to produce eicosanoids. We hypothesized that spinal sPLA2s may contribute to inflammation-induced hyperalgesia. Spinal cord tissue and cerebrospinal fluid were collected from rats for assessment of sPLA2 protein expression and sPLA2 activity. A basal sPLA2 protein expression and activity was detected in spinal cord homogenate (87±17 pmol/min/mg), though no activity could be detected in cisternal cerebrospinal fluid, of naive rats. The sPLA2 activity did not change in spinal cord tissue or cerebrospinal fluid assessed over 8 h after injection of carrageenan into the hind paw. However, the sPLA2 activity observed in spinal cord homogenates was suppressed by addition of LY311727, a selective sPLA2 inhibitor. To determine the role of this spinal sPLA2 in hyperalgesia, we assessed the effects of lumbar intrathecal (IT) administration of LY311727 in rats with chronic IT catheters in three experimental models of hyperalgesia. IT LY311727 (3–30μg) dose-dependently prevented intraplantar carrageenan-induced thermal hyperalgesia and formalin-induced flinching, at doses that had no effect on motor function. IT LY311727 also suppressed thermal hyperalgesia induced by IT injection of substance P (30nmol). Using in vivo spinal microdialysis, we found that IT injection of LY311727 attenuated prostaglandin E2 release into spinal dialysate otherwise evoked by the IT injection of substance P. Taken together, this work points to a role for constitutive sPLA2s in spinal nociceptive processing.
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Key words
phospholipase A2,substance P,formalin,carrageenan,PGE2,spinal cord
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