Contribution of 5- and 12-lipoxygenase products to mechanical hyperalgesia induced by prostaglandin E₂ and epinephrine in the rat

Abstract.

We evaluated the role of lipoxygenase products of arachidonic acid metabolism in mechanical hyperalgesia induced by epinephrine, an agent that directly sensitizes nociceptors to produce mechanical hyperalgesia via three second messenger signaling pathways, protein kinase A (PKA), protein kinase C epsilon (PKCε), and mitogen activated protein kinase (MAPK). Epinephrine hyperalgesia and that induced by a selective activator of PKCε, ψεRACK, were inhibited by nordihydroguaretic acid (NDGA, non-selective lipoxygenase inhibitor), baicalein (BAIC, 12-lipoxygenase inhibitor) and 5, 6-dehydroarachidonic acid (5, 6-dhAA, 5-lipoxygenase inhibitor). NDGA and 5, 6-dhAA inhibited the hyperalgesia associated with activation of the protein kinase A pathway, elicited by the direct-acting hyperalgesic agent prostaglandin E₂ or by the catalytic subunit of protein kinase A. The hyperalgesia produced by active MAPK was not blocked by any of the lipoxygenase inhibitors. Injection of 5- and 12-lipoxygenase produced hyperalgesia that was not antagonized by inhibitors of PKA, PKCε or MAPK. These findings suggest that: (1) lipoxygenase products of arachidonic acid function as second messengers in the peripheral hyperalgesia induced by agents that act directly on primary afferent nociceptors (epinephrine and prostaglandin E₂), (2) products of the 5-lipoxygenase and 12-lipoxygenase pathway are involved in this function, and (3) these lipoxygenase products contribute to hyperalgesia at or downstream of protein kinase A and PKCε.