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

Abstract We recently reported that hyperalgesia induced by the inflammatory mediator prostaglandin E 2 (PGE 2 ) requires intact α1, α3 and β1 integrin subunit function, whereas epinephrine-induced hyperalgesia depends on α5 and β1. PGE 2 -induced hyperalgesia is mediated by protein kinase A (PKA), while epinephrine-induced hyperalgesia is mediated by a combination of PKA, protein kinase Ce (PKCe) and mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK). We hypothesized that inflammatory mediator-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 α1, α3 and β1 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 PKCe agonist depended only on α5 and β1 integrins. Hyperalgesia induced by agonism of MAPK/ERK depended on all four integrin subunits tested (α1, α3, α5 and β1). Finally, disruption of lipid rafts antagonized hyperalgesia induced by PGE 2 and by forskolin, but not that induced by epinephrine. Furthermore, α1 integrin, but not α5, 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.