Membrane-associated prostaglandin E synthase-1 is required for neuropathic pain

It is widely accepted that prostaglandin (PG) E2 is the principal pro-inflammatory prostanoid and plays an important role in inflammatory pain. However whether PGE2 is involved in neuropathic pain remains unknown. PGE2 is produced from arachidonic acid via PGH2 by at least three PGE synthases (PGES), cytosolic PGES (cPGES), and membrane-associated PGES (mPGES)-1 and -2. In the present study, to clarify the involvement of PGE2 and identify PGES mediating neuropathic pain, we applied a neuropathic pain model prepared by L5 spinal nerve transection to mPGES-1 knockout (mPGES-1−/−) mice. Whereas they retained normal nociceptive responses, mPGES-1−/− mice did not exhibit mechanical allodynia and thermal hyperalgesia over a week. These results demonstrate that PGE2 produced by mPGES-1 is involved in neuropathic pain.

[1]  S. Matsumura,et al.  Attenuation of neuropathic pain by the nociceptin/orphanin FQ antagonist JTC‐801 is mediated by inhibition of nitric oxide production , 2003, The European journal of neuroscience.

[2]  J. Johnston,et al.  Renal abnormalities and an altered inflammatory response in mice lacking cyclooxygenase II , 1995, Nature.

[3]  M. Nishizawa,et al.  Central nociceptive role of prostacyclin (IP) receptor induced by peripheral inflammation , 2002, Neuroreport.

[4]  T. Yaksh,et al.  Characterization of time course of spinal amino acids, citrulline and PGE2 release after carrageenan/kaolin-induced knee joint inflammation: a chronic microdialysis study , 1996, Pain.

[5]  K. Sakimura,et al.  Involvement of primary afferent C‐fibres in touch‐evoked pain (allodynia) induced by prostaglandin E2 , 1999, The European journal of neuroscience.

[6]  A. Malmberg,et al.  Antinociceptive actions of spinal nonsteroidal anti-inflammatory agents on the formalin test in the rat. , 1992, The Journal of pharmacology and experimental therapeutics.

[7]  B. Samuelsson,et al.  Identification of human prostaglandin E synthase: a microsomal, glutathione-dependent, inducible enzyme, constituting a potential novel drug target. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[8]  K. Bley,et al.  The role of IP prostanoid receptors in inflammatory pain. , 1998, Trends in pharmacological sciences.

[9]  Jin Mo Chung,et al.  An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat , 1992, PAIN.

[10]  Shizuo Akira,et al.  Lipopolysaccharide-Dependent Prostaglandin E2 Production Is Regulated by the Glutathione-Dependent Prostaglandin E2 Synthase Gene Induced by the Toll-Like Receptor 4/MyD88/NF-IL6 Pathway1 , 2002, The Journal of Immunology.

[11]  植松 智,et al.  Lipopolysaccharide-Dependent Prostaglandin E2 Production Is Regulated by the Glutathione-Dependent Prostaglandin E2 Synthase Gene induced by the Toll-Like Receptor4/MyD88/NF-IL6 Pathway , 2004 .

[12]  Makoto Murakami,et al.  Molecular Identification of Cytosolic Prostaglandin E2 Synthase That Is Functionally Coupled with Cyclooxygenase-1 in Immediate Prostaglandin E2Biosynthesis* , 2000, The Journal of Biological Chemistry.

[13]  O. Hayaishi,et al.  Prostaglandin D2 inhibits prostaglandin E2-induced allodynia in conscious mice. , 1996, The Journal of pharmacology and experimental therapeutics.

[14]  C. Koboldt,et al.  Pharmacological analysis of cyclooxygenase-1 in inflammation. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[15]  Gary J. Bennett,et al.  Painful neuropathy: altered central processing maintained dynamically by peripheral input , 1992, Pain.

[16]  J. Vane,et al.  Nociception in cyclooxygenase isozyme-deficient mice. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[17]  D. Tracey,et al.  Hyperalgesia due to nerve injury: role of prostaglandins , 1999, Neuroscience.

[18]  E. Okuda‐Ashitaka,et al.  Central and peripheral roles of prostaglandins in pain and their interactions with novel neuropeptides nociceptin and nocistatin , 2001, Neuroscience Research.

[19]  J. O'Callaghan,et al.  Chronic neuropathic pain and its control by drugs. , 1997, Pharmacology & therapeutics.

[20]  Seiji Ito,et al.  Identification and characterization of a novel type of membrane-associated prostaglandin E synthase. , 2002, Biochemical and biophysical research communications.

[21]  O. Hayaishi,et al.  Involvement of glutamate receptors in allodynia induced by prostaglandins E2 and F 2α injected into conscious mice , 1994, Pain.

[22]  J. Horn,et al.  Intrathecal ketorolac tromethamine produces analgesia after chronic constriction injury of sciatic nerve in rat , 1996, Canadian journal of anaesthesia = Journal canadien d'anesthesie.

[23]  T. Yaksh,et al.  Cyclooxygenase inhibition and the spinal release of prostaglandin E2 and amino acids evoked by paw formalin injection: a microdialysis study in unanesthetized rats , 1995, The Journal of neuroscience : the official journal of the Society for Neuroscience.