Prostaglandin E2 release evoked by intrathecal dynorphin is dependent on spinal p38 mitogen activated protein kinase.
Spinal dynorphin has been hypothesized to play a pivotal role in spinal sensitization. Although the mechanism of this action is not clear, several lines of evidence suggest that spinal dynorphin-induced hyperalgesia is mediated through an increase in spinal cyclooxygenase products via an enhanced N-methyl-D-aspartate (NMDA) receptor function. Spinal NMDA-evoked prostaglandin release and nociception has been linked to the activation of p38 mitogen activated protein kinase (p38). In the present work, we show that intrathecal delivery of an N-truncated fragment of dynorphin A, dynorphin A 2-17 (dyn2-17), which has no activity at opioid receptors, induced a 8-10-fold increase in phosphorylation of p38 in the spinal cord. The increase in phosphorylated p38 was detected in laminae I-IV of the dorsal horn. Moreover, confocal microscopy showed that the activation of p38 occurred in microglia, but not in neurons or astrocytes. In awake rats, prepared with chronically placed intrathecal loop dialysis catheters, the concentration of prostaglandin E2 in lumbar cerebrospinal fluid was increased 5-fold by intrathecal administration of dyn2-17. Injection of SD-282, a selective p38 inhibitor, but not PD98059, an ERK1/2 inhibitor, attenuated the prostaglanin E2 release. These data, taken together, support the hypothesis that dynorphin, independent of effects mediated by opioid receptors, has properties that can induce spinal sensitization and indicates that dyn2-17 effects may be mediated through activation of the p38 pathway. These studies provide an important downstream linkage where by dynorphin may act through a non-neuronal link to induce a facilitation of spinal nociceptive processing.
Svensson
Camilla I
CI
Department of Anesthesiology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0818, USA. csvensson@ucsd.edu
Hua
Xiao-Ying
XY
Powell
Henry C
HC
Lai
Josephine
J
Porreca
Frank
F
Yaksh
Tony L
TL
D000818:Animals; D015232:Dinoprostone / Q000134:cerebrospinal fluid / Q000378:metabolism*; D004399:Dynorphins / Q000008:administration & dosage / Q000494:pharmacology*; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors; D005419:Flavonoids / Q000378:metabolism; D007278:Injections, Spinal; D008297:Male; D017628:Microglia / Q000201:enzymology; D010446:Peptide Fragments / Q000008:administration & dosage / Q000494:pharmacology*; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
D005419:Flavonoids; D010446:Peptide Fragments; D004399:Dynorphins; C082245:dynorphin (2-17); D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D015232:Dinoprostone; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one