Contribution of 5- and 12-lipoxygenase products to mechanical hyperalgesia induced by prostaglandin E(2) and epinephrine in the rat.
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 (PKCepsilon), and mitogen activated protein kinase (MAPK). Epinephrine hyperalgesia and that induced by a selective activator of PKCepsilon, psiepsilonRACK, 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 E(2) 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, PKCepsilon 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 E(2)), (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 PKCepsilon.
Aley
O
O
NIH Pain Center, University of California, Box #0440, Room #C522, 521 Parnassus Ave, San Francisco, CA 94143-0440, USA. aley@itsa.ucsf.edu
Levine
Jon D
JD
D000322:Adrenergic Agonists / Q000009:adverse effects; D018674:Adrenergic Antagonists / Q000494:pharmacology; D000818:Animals; D001092:Arachidonate 12-Lipoxygenase / Q000378:metabolism*; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism*; D015232:Dinoprostone / Q000009:adverse effects*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004837:Epinephrine / Q000009:adverse effects*; D006930:Hyperalgesia / Q000139:chemically induced / Q000201:enzymology / Q000378:metabolism*; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000009:adverse effects; D010120:Oxytocics / Q000009:adverse effects; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology; D011493:Protein Kinase C / Q000009:adverse effects; D051744:Protein Kinase C-epsilon; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015290:Second Messenger Systems / Q000502:physiology
D000322:Adrenergic Agonists; D018674:Adrenergic Antagonists; D016859:Lipoxygenase Inhibitors; D010120:Oxytocics; D047428:Protein Kinase Inhibitors; D001092:Arachidonate 12-Lipoxygenase; D001094:Arachidonate 5-Lipoxygenase; D011494:Protein Kinases; C497257:Prkce protein, rat; D011493:Protein Kinase C; D051744:Protein Kinase C-epsilon; D020928:Mitogen-Activated Protein Kinases; D015232:Dinoprostone; D004837:Epinephrine