Spinal phospholipase A 2 in inflammatory hyperalgesia: Role of the small, secretory phospholipase A 2

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 A 2s (sPLA 2s) 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 sPLA 2s may contribute to inflammation-induced hyperalgesia. Spinal cord tissue and cerebrospinal fluid were collected from rats for assessment of sPLA 2 protein expression and sPLA 2 activity. A basal sPLA 2 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 sPLA 2 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 sPLA 2 activity observed in spinal cord homogenates was suppressed by addition of LY311727, a selective sPLA 2 inhibitor. To determine the role of this spinal sPLA 2 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 E 2 release into spinal dialysate otherwise evoked by the IT injection of substance P. Taken together, this work points to a role for constitutive sPLA 2s in spinal nociceptive processing.