title: Topical bicuculline to the rat spinal cord induces highly localized allodynia that is mediated by spinal prostaglandins.
abstract: The purpose of this study was to investigate the allodynic effect of bicuculline (BIC) given topically to the dorsal surface of the rat spinal cord, and to determine if spinal prostaglandins (PGs) mediate the allodynic state arising from spinal GABA(A)-receptor blockade. Male Sprague-Dawley rats (325-400 g) were anaesthetized with halothane and maintained with urethane for the continuous monitoring of blood pressure (MAP), heart rate (HR) and cortical electroencephalogram (EEG). A laminectomy was performed to expose the dorsal surface of the spinal cord. Unilateral application of BIC (0.1 microg in 0.1 microl) to the L5 or L6 spinal segment induced a highly localized allodynia (e.g. one or two digits) on the ipsilateral hind paw. Thus, hair deflection (brushing the hair with a cotton-tipped applicator) in the presence, but not absence of BIC, evoked an increase in MAP and HR, abrupt motor responses (MR; e.g. withdrawal of the hind leg, kicking, and/or scratching) on the affected side, and desynchrony of the EEG. BIC-allodynia was dose-dependent, yielding ED(50)'s (95% CI's) of 45 ng (31-65) for MAP; 68 ng (46-101) for HR and 76 ng (60-97) for MR. Allodynia was sustained for up to 2 h with repeated BIC application without any detectable change in the location or area of peripheral sensitization. Pretreatment with either the EP(1)- receptor antagonist, SC-51322, the cyclooxygenase (COX)-2 selective inhibitor, NS-398, or the NMDA-receptor antagonist, AP-7, inhibited BIC-allodynia in a dose-dependent manner. The results demonstrate: (a) BIC, applied to the dorsal surface of the spinal cord, induces highly localized allodynia; (b) this effect can be sustained with repeated BIC application; (c) it is evoked by NMDA-dependent afferent input; (d) spinal PGs are synthesized by constitutive COX-2 during BIC-allodynia; and (e) spinal PGs contribute to the abnormal processing of tactile input via spinal EP1-receptors.
authors.affiliation: School of Pharmacy and Division of Basic Medical Sciences, Faculty of Medicine, Memorial University of Newfoundland, St. John's, Newfoundland, A1B 3V6, Canada.
authors.forename: Zizhen
authors.initials: Z
authors.lastname: Zhang
authors.forename: Michael P
authors.initials: MP
authors.lastname: Hefferan
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Loomis
mesh_terms: D015763:2-Amino-5-phosphonovalerate / Q000031:analogs & derivatives / Q000494:pharmacology; D000287:Administration, Topical; D000818:Animals; D001640:Bicuculline / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004569:Electroencephalography / Q000187:drug effects; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology*; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D008297:Male; D009046:Motor Neurons / Q000187:drug effects / Q000502:physiology; D009578:Nitrobenzenes / Q000494:pharmacology; D010147:Pain Measurement / Q000187:drug effects* / Q000379:methods; D020671:Posterior Horn Cells / Q000187:drug effects* / Q000502:physiology; D011453:Prostaglandins / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018078:Receptors, Prostaglandin E / Q000037:antagonists & inhibitors; D058306:Receptors, Prostaglandin E, EP1 Subtype; D013116:Spinal Cord / Q000187:drug effects / Q000502:physiology; D013449:Sulfonamides / Q000494:pharmacology; D014110:Touch / Q000187:drug effects* / Q000502:physiology
chemical_list: D016861:Cyclooxygenase Inhibitors; D018691:Excitatory Amino Acid Antagonists; D018756:GABA Antagonists; D009578:Nitrobenzenes; D011453:Prostaglandins; C545637:Ptger1 protein, rat; D018078:Receptors, Prostaglandin E; D058306:Receptors, Prostaglandin E, EP1 Subtype; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D015763:2-Amino-5-phosphonovalerate; C031231:2-amino-7-phosphonoheptanoic acid; D001640:Bicuculline