Cyclooxygenase inhibition and the spinal release of prostaglandin E2 and amino acids evoked by paw formalin injection: a microdialysis study in unanesthetized rats

Abstract

Injection of formalin into the hind paw evokes a biphasic flinching of the injured paw. Pharmacological characterization of this behavior has implicated the spinal release of excitatory amino acids (EAAs) and cyclooxygenase (COX) products. To address this hypothesis, we examined the effect of paw formalin injection on release of EAAs and prostaglandin E2-like immunoreactivity (PGE2-LI) from the spinal cord in unanesthetized rats using a dialysis probe placed in the lumbar subarachnoid space. To assess the contribution of spinal COX products, the effects of S(+)- and R(-)-ibuprofen (active and inactive COX inhibitors) were examined. Paw formalin injection evoked a biphasic spinal release of PGE2-LI with an increase above resting concentrations of 110% in the 0-10 min sample, and of 83% in the 20-30 min sample. Significantly increased release of glutamate (Glu; 110%) and aspartate (Asp; 112%) was only observed in the 0-10 min sample. Saline injection into the paw had no effect on behavior, PGE2-LI, or EAA release. Intraperitoneal administration of 10 mg/kg, but not 1 mg/kg, S(+)-ibuprofen reduced paw flinching, blocked the elevated levels of PGE2-LI, and suppressed Glu and Asp release to 50% of control. Intrathecal delivery of 10 micrograms, but not 1 microgram, S(+)-ibuprofen also suppressed formalin-induced behavior, PGE2-LI, Glu, and Asp release. R(-)-ibuprofen showed no effect on formalin-induced behaviors or spinal release. These data demonstrate that paw formalin injection produces spinal release of PGE2-LI corresponding to the biphasic behavioral response and that the evoked release is blocked by antinociceptive doses of COX inhibitors.(ABSTRACT TRUNCATED AT 250 WORDS)

Secondary hyperalgesia in the rat first degree burn model is independent of spinal cyclooxygenase and nitric oxide synthase

“…The decrease in withdrawal threshold plateaued for two hours post injury and still remained depressed compared to baseline at the 150 min timepoint. This dose of (S) -(+) -ibuprofen is sufficient to reduce phase 1 and 2 of the formalin test and to reduce intraplantar formalin induced increases in PGE 2 (Malmberg and Yaksh, 1995); a dose of 5.6 μg (S ) -(+) -ibuprofen is sufficient to delay development of thermal hyperalgesia induced by intraplantar carageenan, while 16 μg (Dirig et al, 1998) substantially reduced hyperalgesia over a two h period. Increasing the pretreatment dose of (S) -(+) -ibuprofen to 30 μg (N=8) in the burn model was associated with a modest anti-allodynia.…”

Glucocorticoid-Induced Leucine Zipper (GILZ) Over-Expression in T Lymphocytes Inhibits Inflammation and Tissue Damage in Spinal Cord Injury

“…Many signals and stimuli (including traumatic events) are responsible for the inflammatory process activation and development [1]. A post-traumatic inflammatory reaction plays an important role in the secondary injury process that develops after spinal cord injury (SCI) [2].…”

Effect of Acute Systemic Inflammatory Response and Cytokines on the Transcription of the Genes Encoding Cyclooxygenase Enzymes (COX‐1 and COX‐2) in the Rat Brain

“…Moreover, arachidonic acid metabolism also participates in the endotoxin-and turpentine-induced adrenocortical activation in the rat (Smith et al, 1994;Turnbull and Rivier, 1996). Subcutaneous injection of a dilute formalin solution into the hind paw produced spinal release of prostaglandin E 2 (PGE2), whereas cyclooxygenase inhibition via ibuprofen administration suppressed by 50% the release of excitatory amino acids within the spinal dorsal horn (Malmberg and Yaksh, 1995). It has also been proposed that the mechanisms of action underlying the febrile response to endotoxin and cytokines involve the cyclooxygenase pathway and the localized diencephalic synthesis of PGs (Sirko et al, 1989;Komaki et al, 1992;LopezValpuesta and Myers, 1994).…”