title: Morphological and pharmacological evidence for the role of peripheral prostaglandins in the pathogenesis of neuropathic pain.
abstract: Inflammatory mediators produced in the injured nerve have been proposed as contributing factors in the development of neuropathic pain. Prostaglandins (PGs) are probably included in these important inflammatory mediators. In the present study, 2 and 4 weeks following partial sciatic nerve ligation (PSNL), we observed a dramatic increase in the prostaglandin synthesizing enzyme cyclooxygenase (COX)2-immunoreactive (IR) cell profiles in the injury site and adjacent region. Some of these COX2-IR cells were identified as macrophages because they coexpressed ED1. None of these COX2-IR cell profiles coexpressed the Schwann cell marker S100. In the contralateral sciatic nerve and sciatic nerve from normal rats, we failed to observe any of these COX-IR cell profiles. We also observed COX1-IR cell profiles (presumably Langerhans cells) in the epidermis of the footpad of both normal and PSNL rats. Interestingly, a greater number of COX1-IR cell profiles were observed in the epidermis of the ipsilateral footpad of PSNL rats. Local injection of ketorolac, a nonselective COX inhibitor, into the ipsilateral plantar side or into the injury site of the sciatic nerve, effectively reversed the tactile allodynia induced by PSNL for > 5 days. Intraperitoneal or intramuscular injection of ketorolac had a similar but shorter antiallodynic effect. Intraplantar or peri-neural injection of ketorolac dramatically suppressed the PSNL-induced increase in the phosphorylation of a transcription factor cAMP response element binding protein (CREB) in the ipsilateral dorsal horn of L4 and L5 spinal cord of PSNL rats. Intraplantar or peri-neural injection of ketorolac at the time of lesion did not prevent mechanical hypersensitivity but reduced it with a slow onset 3 weeks after lesion. Our data suggest that PSNL induces over-production of PGs in peripheral tissues and that PGs probably sensitize nociceptors and are involved in central plasticity and sensitization at the spinal cord level, thus contributing to the maintenance of tactile allodynia.
authors.affiliation: Pain Mechanism Laboratory, Department of Anaesthesiology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA. wma@wfubmc.edu
authors.forename: Weiya
authors.initials: W
authors.lastname: Ma
authors.forename: James C
authors.initials: JC
authors.lastname: Eisenach
mesh_terms: D000818:Animals; D017362:Cyclic AMP Response Element-Binding Protein / Q000187:drug effects / Q000378:metabolism; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D053331:Ectodysplasins; D006930:Hyperalgesia / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D007249:Inflammation / Q000378:metabolism* / Q000503:physiopathology; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020910:Ketorolac / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D009437:Neuralgia / Q000378:metabolism* / Q000503:physiopathology; D010523:Peripheral Nervous System Diseases / Q000378:metabolism* / Q000503:physiopathology; D020671:Posterior Horn Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D011453:Prostaglandins / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D012584:Sciatic Nerve / Q000293:injuries / Q000378:metabolism* / Q000473:pathology; D012867:Skin / Q000276:immunology / Q000473:pathology / Q000503:physiopathology; D015854:Up-Regulation / Q000502:physiology*
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D053331:Ectodysplasins; D007527:Isoenzymes; D008565:Membrane Proteins; D011453:Prostaglandins; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C496513:Ptgs1 protein, rat; D020910:Ketorolac