title: A stable prostacyclin analog enhances ectopic activity in rat sensory neurons following neuropathic injury.
abstract: Prostanoids sensitize sensory afferents during inflammation. However, their role in neuropathic pain is still unclear. We analyzed the actions of prostanoids, non-selective (indomethacin) or selective (celecoxib and NS-398) cyclooxygenase-2 (COX or COX-2) inhibitors, on the ectopic activity of dorsal 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 ventilated adult male Sprague-Dawley rats whose sciatic nerve had been transected. PGD(2), PGE(2), PGF(2alpha), carbaprostacyclin (cPGI(2); a stable prostacyclin 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 cPGI(2) significantly increased the DRG and DH activity in a dose-dependent manner, with ED(50) values of 0.05 (0.01-0.96) and 0.69 (0.11-1.04) mg/kg, respectively. 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.) increased 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 and 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 indomethacin, but not celecoxib or NS-398, on ectopic activity may suggest that a tonic generation of PGI(2) by COX-1 could contribute to neuropathic pain.
authors.affiliation: CNS Therapy Area, Roche Bioscience, 3401 Hillview Avenue, Palo Alto, CA 94304, USA. imelda.omana-zapata@roche.com
authors.forename: I
authors.initials: I
authors.lastname: Omana-Zapata
authors.forename: K R
authors.initials: KR
authors.lastname: Bley
mesh_terms: D000200:Action Potentials / Q000187:drug effects* / Q000502:physiology; D000818:Animals; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004347:Drug Interactions / Q000502:physiology; D005727:Ganglia, Spinal / Q000187:drug effects* / Q000503:physiopathology; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D007249:Inflammation / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D009437:Neuralgia / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology*; D009475:Neurons, Afferent / Q000187:drug effects* / Q000502:physiology; D010525:Peripheral Nerves / Q000473:pathology / Q000503:physiopathology* / Q000601:surgery; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011453:Prostaglandins / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011982:Receptors, Prostaglandin / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D011453:Prostaglandins; D011982:Receptors, Prostaglandin; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases