Spinal phospholipase A2 in inflammatory hyperalgesia: Role of the small, secretory phospholipase A2

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(2)s (sPLA(2)s) 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(2)s 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 (3-30 microg) 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 (30 nmol). 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(2)s in spinal nociceptive processing.

Physiological Roles of Group X-secreted Phospholipase A2 in Reproduction, Gastrointestinal Phospholipid Digestion, and Neuronal Function

“…These prostanoids stimulate a population of TRPV1-positive, C-fiber DRG neurons to release peptide neurotransmitters (80). Observations that the late, prostanoid-dependent phase of chemicalinduced pain is suppressed by a pan-sPLA 2 inhibitor (81) and that the noxious heat-evoked, TRPV1-dependent response does not depend on prostanoids (80) appear to be compatible with our present findings. LPA, which is produced from LPC by autotaxin, plays a role in neuropathic pain via its receptor LPA 1 by promoting demyelination of A-fibers and subsequent direct contact between A-and C-fibers (82,83).…”

Systemic and Intrathecal Effects of a Novel Series of Phospholipase A2 Inhibitors on Hyperalgesia and Spinal Prostaglandin E2 Release

“…Western blotting and reverse transcription-polymerase chain reaction have shown that group IVA cPLA 2 , group VIA iPLA 2 , and secretory PLA 2 (groups IIA and V) are constitutively expressed in the spinal cord (Sapirstein and Bonventre, 2000;Lucas et al, 2005;Svensson et al, 2005b). The role of these respective isoforms has been difficult to assess given the lack of potent and selective inhibitors.…”

“…An important element of prostaglandin (PG) synthesis is phospholipase A 2 (PLA 2 ) because it is required to generate arachidonic acid, which is the substrate for COX-mediated prostanoid formation. In recent work, we have shown the presence of constitutive mRNA and protein in the spinal cord for group IVA calcium-dependent PLA 2 (cPLA 2 ) and group VIA calcium-independent PLA 2 (iPLA2) and groups II and V secretory PLA 2 forms (Lucas et al, 2005;Svensson et al, 2005b). Inhibition of group IV cPLA 2 but not group VI iPLA 2 isoforms using i.t.-delivered agents suggested a role for group IV cPLA 2 , but not group VI iPLA 2 (Lucas et al, 2005), in inflammation-evoked hyperalgesia.…”

Liberating Chiral Lipid Mediators, Inflammatory Enzymes, and LIPID MAPS from Biological Grease

“…For example, inflammatory hyperalgesia and various forms of pain induce essential bioactive lipid production in the spinal cord and spinal fluid. Over the years with my UCSD colleague Tony Yaksh, we've characterized PLA 2 enzymes in spinal cord and spinal fluid (178,179) as well as examining the role of resulting eicosanoids (180). This included the discovery of the novel role of spinal 12-lipoxygenase-derived hepoxilins A 3 and B 3 , which activate the TRPV1 and TRPA1 receptors, in inflammatory hyperalgesia (181).…”