ono-8713 and Disease-Models--Animal

Neuropathic pain produced by damage to or dysfunction of the nervous system is a common and severely disabling state that affects millions of people worldwide. Recent evidence indicates that activated microglia are key cellular intermediaries in the pathogenesis of neuropathic pain and that ATP serves as the mediator. However, the in vivo mechanism underlying the retention of activated microglia in the injured region has not yet been completely elucidated. Prostaglandin E(2) (PGE(2)) is the principal proinflammatory prostanoid and plays versatile roles by acting via four PGE receptor subtypes, EP1-EP4. In the present study, we investigated the role of PGE(2) in spinal microglial activation in relation to neuropathic pain by using genetic and pharmacological methods. Mice deficient in microsomal prostaglandin E synthase-1 impaired the activation of microglia and the NMDA-nitric oxide (NO) cascade in spinal neurons in the dorsal horn and did not exhibit mechanical allodynia after peripheral nerve injury. The intrathecal injection of indomethacin, a nonsteroidal anti-inflammatory drug, ONO-8713, a selective EP1 antagonist, or 7-nitroindole, a neuronal NO synthase inhibitor, attenuated mechanical allodynia and the increase in activated microglia observed in the established neuropathic-pain state. We further demonstrated that ATP-induced microglial migration was blocked in vitro by PGE(2) via EP2 and by S-nitrosoglutathione, an NO donor. Taken together, the present study suggests that PGE(2) participated in the maintenance of neuropathic pain in vivo not only by activating spinal neurons, but also by retaining microglia in the central terminals of primary afferent fibers via EP2 subtype and via EP1-mediated NO production.

Topics: Adenosine Triphosphate; Animals; Cell Movement; Cerebral Cortex; Cinnamates; Dinoprostone; Disease Models, Animal; Enzyme Inhibitors; Gene Expression Regulation, Enzymologic; Hyperalgesia; Indazoles; Intramolecular Oxidoreductases; Male; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Mice, Knockout; Microglia; Neuralgia; Neurons; Nitric Oxide; Nitric Oxide Donors; Nitric Oxide Synthase Type I; Prostaglandin-E Synthases; S-Nitrosoglutathione; Spinal Cord; Spinal Nerves

The effect of an EP1 receptor antagonist on pain-related behavior induced by nucleus pulposus (NP) applied to the dorsal root ganglion (DRG) in rats was investigated.. We investigated pain-related behavior, the amount of prostaglandin E2 (PGE2), and neural damage to the DRG after application of NP to the DRG after administration of an EP1 receptor antagonist.. PGE2 induces mechanical allodynia and hyperalgesia, which are mediated by PGE2 receptors. EP1 is one of the PGE2 receptor subtypes. An EP1 antagonist reduces hyperalgesia, allodynia, and c-fos expression in the rat chronic nerve constriction model.. Sprague-Dawley rats (n = 103) were used. Animals receiving NP were divided into three experimental groups (n = 12 in each group): saline, high-dose (5 mg/kg) EP1 receptor antagonist (RA), and low-dose (2.5 mg/kg) EP1-RA (orally once daily for 5 days). Animals in the sham group did not receive NP. Von Frey tests were used for pain-behavior testing. The amount of PGE2 in DRG and the number of activating transcription factor-3 (ATF3) immunoreactive positive cells were compared among groups.. The mechanical thresholds in the three groups decreased 7 days after surgery (just before treatment). The threshold in both the high- and low-dose EP1-RA groups increased at 11 days (5 days after treatment) and continued for 14 days. The thresholds in both the low- and high-dose EP1-RA groups increased significantly compared with the saline group (P < 0.05). The amount of PGE2 was significantly increased in the NP group compared with the sham and naïve animals after application of NP. ATF3 expression was increased by NP but was not increased after administration of the EP1-RA.. An EP1 receptor antagonist improves pain-related behavior in the rat model and might be a potential agent to improve pain-related behavior in patients with lumbar disc herniation.

Topics: Activating Transcription Factor 3; Analgesics; Animals; Behavior, Animal; Cinnamates; Dinoprostone; Disease Models, Animal; Female; Ganglia, Spinal; Intervertebral Disc; Intervertebral Disc Displacement; Lumbar Vertebrae; Pain Measurement; Pain Threshold; Rats; Rats, Sprague-Dawley; Receptors, Prostaglandin E, EP1 Subtype; Time Factors