Inhibition of spinal prostaglandin synthesis early after L5/L6 nerve ligation prevents the development of prostaglandin-dependent and prostaglandin-independent allodynia in the rat

Prostaglandins, synthesized in the spinal cord in response to noxious stimuli, are known to facilitate nociceptive transmission, raising questions about their role in neuropathic pain. The current study tested the hypothesis that spinal nerve ligation-induced allodynia is composed of an early prostaglandin-dependent phase, the disruption of which prevents allodynia. Male Sprague-Dawley rats, fitted with intrathecal drug delivery or microdialysis catheters, underwent left L5-L6 spinal nerve ligation or sham surgery. Paw withdrawal threshold, brush-evoked behavior, and the concentration of prostaglandin E2 (PGE2) in spinal cerebrospinal fluid ([PGE2]dialysate) were determined for up to 24 days. PGE2-evoked glutamate release from spinal slices was also determined. Paw withdrawal threshold decreased from at least 15 g (control) to less than 4 g, beginning 1 day after ligation. Brushing the affected hind paw evoked nociceptive-like behavior and increased [PGE2]dialysate (up to 257 +/- 62% of baseline). There was no detectable change in basal [PGE2]dialysate from preligation values. The EC50 of PGE2-evoked glutamate release (2.4 x 10-11 M, control) was significantly decreased in affected spinal segments of allodynic rats (8.9 x 10-15 M). Treatment with intrathecal S(+)-ibuprofen or SC-560, beginning 2 h after ligation, prevented the decrease in paw withdrawal threshold, the brush-evoked increase in [PGE2]dialysate, and the change in EC50 of PGE2-evoked glutamate release. R(-)-ibuprofen or SC-236 had no effect. The results of this study provide solid evidence that spinal prostaglandins, synthesized by cyclooxygenase-1 in the first 4-8 h after ligation, are critical in the pathogenesis of prostaglandin-dependent and prostaglandin-independent allodynia and that their early pharmacologic disruption affords protection against this neuropathic state in the rat.