A study of the role of spinal prostaglandins and nitric oxide in the spinal nerve ligation model of neuropathic pain

Hefferan, Michael Patrick (2004) A study of the role of spinal prostaglandins and nitric oxide in the spinal nerve ligation model of neuropathic pain. Doctoral (PhD) thesis, Memorial University of Newfoundland.

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Pain arising from nerve injury is often resistant to conventional analgesics and is believed to have mechanisms distinct from those of normal nociception. To determine if spinal prostaglandins (PG) contribute to tactile allodynia, male, Sprague-Dawley rats were fitted with either i.t. microdialysis or drug delivery catheters 3 days before tight ligation of the left lumbar 5/6 spinal nerves. Ligated rats developed tactile allodynia within 24 h, as evidenced by a decrease in paw withdrawal thresholds (PWT) in the affected hind paw (<4 g vs >15 g control). Allodynia was also characterized by a significant increase in the evoked release of PGE₂. Thus, brushing the plantar surface of the affected hind paw with a cotton-tipped applicator, up to 5 days post-ligation, increased the CSF level of PGE₂ (measured using intrathecal microdialysis - [PGE₂]dialysate) compared to the pre-stimulus control period. In vitro, spinal cord slices were used to determine the effect of PGE₂ on glutamate release. The EC₅₀ of PGE₂-evoked glutamate release (2.4x10⁻¹¹ M; control) was significantly decreased in affected spinal segments of allodynic rats (8.9x10⁻¹⁵ M). In a separate group of rats and beginning 2 days after ligation, the acute i.t. injection of S(+)-ibuprofen (non-selective cyclooxygenase inhibitor), SC-51322 (prostaglandin E receptor antagonist), SC-236 (cyclooxygenase-2 selective inhibitor), or SC-560 (cyclooxygenase-1 selective inhibitor) significantly reversed allodynia. The nitric oxide synthase inhibitor L-NAME had a similar effect to S(+)-ibuprofen, and was subsequently tested using isobolographic analysis. The co-administration of both inhibitors resulted in an additive anti-allodynic effect. To investigate spinal PG as possible early triggers of allodynia, we studied the effects of early post-injury treatment with isozyme selective and non-selective COX inhibitors. Treatment with i.t. S(+)-ibuprofen or SC-560, beginning 2 h after ligation, prevented the decrease in PWT, the brush-evoked increase in [PGE1]dialysate, and the change in EC₅₀ of PGE₂-evoked glutamate release. In contrast, lot. R(-)-ibuprofen or SC-236 had no effect. The results of this study suggest that: a) spinal PG synthesis is triggered by spinal nerve ligation; b) pharmacological disruption of PG synthesis or signaling can transiently reverse established allodynia; c) spinal PG, synthesized by cyclooxygenase (COX)-1 in the first 4-Sh after ligation, is a critical trigger of allodynia; d) spinal nitric oxide appears to act in concert with PG to mediate allodynia. Together, it appears that allodynia resulting from L51L6 spinal nerve ligation is comprised of an initial, time-limited, PG-dependent stage (characterized by brush-evoked increases in [PGE₂]dialysate and sensitivity to COX-2 inhibitors) and long-term, PG-independent allodynia. The ability of appropriate COX inhibitors to prevent both stages suggests that the two are related.

Item Type: Thesis (Doctoral (PhD))
URI: http://research.library.mun.ca/id/eprint/10644
Item ID: 10644
Additional Information: Bibliography: leaves 122-146.
Department(s): Medicine, Faculty of
Date: 2004
Date Type: Submission
Library of Congress Subject Heading: Allodynia; Nitric oxide; Pain--Pathophysiology; Pain--Treatment; Prostaglandins.
Medical Subject Heading: Nitric Oxide--therapeutic use; Pain--physiopathology; Pain Management; Prostaglandins--therapeutic use.

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