A stable prostacyclin analog enhances ectopic activity in rat sensory neurons following neuropathic injury

Prostanoids sensitize sensory afferents during inflammation. However, their role in neuropathic pain is still unclear. We analyzed the actions of pros tanoids, non-selective (indomethacin) or selective (celecoxib and NS-398) c yclooxygenase-2 (COX or COX-2) inhibitors, on the ectopic activity of dorsa l root ganglia (DRG) and dorsal horn (DH) neurons in a model of neuropathic injury. Extracellular recordings of DRG and DH neurons and cardiovascular measurements were performed on anesthetized, paralyzed and artificially ven tilated adult male Sprague-Dawley rats whose sciatic nerve had been transec ted. PGD(2), PGE(2), PGF(2 alpha), carbaprostacyclin (cPGI(2); a stable pro stacyclin analog), and carbocyclic thromboxane (cTXA(2)) were administered at cumulative doses (0.0001-5 mg/kg, i.p.) at 5 or 10 min intervals. Only c PGI(2) significantly increased the DRG and DH activity in a dose-dependent manner, with ED50 values of 0.05 (0.01-0.96) and 0.69 (0.11-1.04) mg/kg, re spectively. The other prostanoids did not significantly increase activity, although they reduced heart rate for up to 5 min following administration. Time course experiments with single doses of cPGI(2) (1 mg/kg, i.v.) increa sed DH discharge rate 3-17 min after injection. Indomethacin (3 mg/kg, s.c. ), but not celecoxib or NS-398 (both at 6 mg/kg, s.c.), reduced both DRG an d DH activity. Our results indicate that cPGI(2) excites DRG and DH neurons of neuropathic rats, and may suggest a role for IP prostanoid receptors in pain episodes associated with nerve injury. The inhibitory effect of indom ethacin, but nut celecoxib or NS-398, on ectopic activity may suggest that a tonic generation of PGI(2) by COX-1 could contribute to neuropathic pain. (C) 2001 Elsevier Science B.V. All rights reserved.