Primary afferent second messenger cascades interact with specific integrin subunits in producing inflammatory hyperalgesia

We recently reported that hyperalgesia induced by the inflammatory mediator prostaglandin E-2 (PGE(2)) requires intact alpha 1, alpha 3 and beta 1 integrin subunit function, whereas epinephrine-induced hyperalgesia depends on alpha 5 and beta 1. PGE(2)-induced hyperalgesia is mediated by protein kinase A (PKA), while epinephrine-induced hyperalgesia is mediated by a combination of PKA, protein kinase C epsilon (PKC epsilon) and mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK). We hypothesized that inflammatory inediator-induced hyperalgesia involves specific interactions between different Subsets of integrin subunits and particular second messenger species. In the present study. function-blocking anti-integrin antibodies and antisense oligodeoxynucleotides were used to elucidate these interactions in rat. Hyperalgesia produced by an activator of adenylate cyclase (forskolin) depended on alpha 1, alpha 3 and beta 1 integrins. However, hyperalgesia induced by activation of the cascade at a point farther downstream (by cAMP analog or PKA catalytic subunit) was independent of any integrins tested. In contrast. hyperalgesia induced by a specific PKC epsilon agonist depended only on alpha 5 and beta 1 integrins. Hyperalgesia induced by agonism of MAPK/ERK depended on all four integrin subunits tested (alpha 1, alpha 3, alpha 5 and beta 1). Finally, disruption of lipid rafts antagonized hyperalgesia induced by PGE(2) and by forskolin, but not that induced by epinephrine. Furthermore, alpha 1 integrin, but not alpha 5, was present in detergent-resistant membrane fractions (which retain lipid raft components). These observations suggest that integrins play a critical role in inflammatory pain by interacting with components of second messenger cascades that mediate inflammatory hyperalgesia, and that such interaction with the PGE(2)-activated pathway may be organized by lipid rafts. (c) 2005 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.