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.