Peripheral inhibition of glutaminase reduces carrageenan-induced Fos expression in the superficial dorsal horn of the rat.
In inflamed tissue, the levels of the excitatory amino acid glutamate are increased. Glutamate sensitizes peripheral axons of primary afferent neurons during inflammation leading to decreased firing threshold and hyperexcitability. One proposed source of glutamate is the primary afferent. Antagonizing glutamate receptors on peripheral axons of primary afferents during inflammation provides analgesia in animals and humans. The enzyme glutaminase is used by primary sensory neurons to convert glutamine to glutamate, and peripheral inhibition of glutaminase with 6-diazo-5-oxo-l-norleucine (DON) provides long-lasting analgesia during inflammation. In this study, we measured the effects of glutaminase inhibition on carrageenan-induced spinal Fos expression. Rats were given intraplantar injections of carrageenan and treated locally with either vehicle or DON. After 3h of inflammation, hind paw swelling and spinal expression of Fos were examined. CellProfiler was used to automate Fos nuclei counting in five laminar groupings in the spinal cord (I-II, III-IV, V-VI, VII-IX, X). Carrageenan increased hind paw thickness by approximately 70% and spinal Fos expression in superficial (I-II) and deep (V-VI) laminae by 10-fold and 5-fold, respectively. Treatment with DON reduced hind paw swelling by approximately 13% and suppressed Fos expression in the laminae I-II by approximately 54%, but not the deep laminae. Our results further support the notion of glutamate as a peripheral inflammatory mediator and indicate that glutaminase should be considered as a novel therapeutic target for treatment of inflammatory pain.
Hoffman
Ernest M
EM
Department of Anatomy and Cell Biology, Oklahoma State University Center for Health Sciences, Tulsa, OK, USA.
Miller
Kenneth E
KE
D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D002351:Carrageenan; D003980:Diazooxonorleucine / Q000494:pharmacology*; D004487:Edema / Q000139:chemically induced / Q000378:metabolism*; D018698:Glutamic Acid / Q000096:biosynthesis; D005972:Glutaminase / Q000037:antagonists & inhibitors*; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism; D009411:Nerve Endings / Q000378:metabolism; D020671:Posterior Horn Cells / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000187:drug effects* / Q000378:metabolism
D000700:Analgesics; D016760:Proto-Oncogene Proteins c-fos; D003980:Diazooxonorleucine; D018698:Glutamic Acid; D002351:Carrageenan; D005972:Glutaminase