Prostanoid receptor EP1 and Cox-2 in injured human nerves and a rat model of nerve injury: a time-course study

Abstract

BackgroundRecent studies show that inflammatory processes may contribute to neuropathic pain. Cyclooxygenase-2 (Cox-2) is an inducible enzyme responsible for production of prostanoids, which may sensitise sensory neurones via the EP1 receptor. We have recently reported that while macrophages infiltrate injured nerves within days of injury, they express increased Cox-2-immunoreactivity (Cox-2-IR) from 2 to 3 weeks after injury. We have now investigated the time course of EP1 and Cox-2 changes in injured human nerves and dorsal root ganglia (DRG), and the chronic constriction nerve injury (CCI) model in the rat.MethodsTissue sections were immunostained with specific antibodies to EP1, Cox-2, CD68 (human macrophage marker) or OX42 (rat microglial marker), and neurofilaments (NF), prior to image analysis, from the following: human brachial plexus nerves (21 to 196 days post-injury), painful neuromas (9 days to 12 years post-injury), avulsion injured DRG, control nerves and DRG, and rat CCI model tissues. EP1 and NF-immunoreactive nerve fibres were quantified by image analysis.ResultsEP1:NF ratio was significantly increased in human brachial plexus nerve fibres, both proximal and distal to injury, in comparison with uninjured nerves. Sensory neurones in injured human DRG showed a significant acute increase of EP1-IR intensity. While there was a rapid increase in EP1-fibres and CD-68 positive macrophages, Cox-2 increase was apparent later, but was persistent in human painful neuromas for years. A similar time-course of changes was found in the rat CCI model with the above markers, both in the injured nerves and ipsilateral dorsal spinal cord.ConclusionDifferent stages of infiltration and activation of macrophages may be observed in the peripheral and central nervous system following peripheral nerve injury. EP1 receptor level increase in sensory neurones, and macrophage infiltration, appears to precede increased Cox-2 expression by macrophages. However, other methods for detecting Cox-2 levels and activity are required. EP1 antagonists may show therapeutic effects in acute and chronic neuropathic pain, in addition to inflammatory pain.

Expression of cyclooxygenase-2 in urinary bladder in rats with cyclophosphamide-induced cystitis

“…A number of studies have demonstrated COX-2-IR in nerves (i.e., endoneurium) in response inflammatory stimuli alone or as a result of neural injury (13,31). In the present study, we have confirmed that COX-2-IR is present in nerve in the suburothelial plexus and that COX-2-IR nerve fibers increase in density in the trigone region of the urinary bladder with acute and chronic CYP-induced cystitis.…”

Sensory and Signaling Mechanisms of Bradykinin, Eicosanoids, Platelet-Activating Factor, and Nitric Oxide in Peripheral Nociceptors

“…COX-2 upregulation (peaking 4 -6 wk after injury) in the injured nerve was shown following CCI in the rat sciatic nerve or after surgical injury of human nerves (166). In these two models, an early EP 1 receptor upregulation (appearing from day 5 on) in the injured nerve fibers and the corresponding DRGs was revealed together with an early macrophage infiltration into the injured nerve that was followed by COX-2 upregulation only later (165). In the CCI model, EP 1 and EP 4 receptor upregulation was revealed in infiltrating macrophages and the Schwann cells of the injured sciatic nerve (778).…”

Insights from experimental studies into allodynia and its treatment

“…These results suggest that spinal cyclooxygenase contributes to central sensitization during migraine. Current studies show that COX-2 is upregulated on microglia/macrophages in chronic pain models [51].…”