A study of spinal prostaglandins in experimental allodynia

Zhang, Zizhen (2001) A study of spinal prostaglandins in experimental allodynia. Masters thesis, Memorial University of Newfoundland.

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    Available under License - The author retains copyright ownership and moral rights in this thesis. Neither the thesis nor substantial extracts from it may be printed or otherwise reproduced without the author's permission.
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Abstract

Cumulative evidence indicates that the release of spinal prostaglandins (PGs) is increased in hyperalgesia and persistent pain states following peripheral inflammation or injury, events that are associated with repetitive C-fiber stimulation. Non-steroidal anti-inflammatory drugs (NSAIDs), given intrathecally (i.t), inhibited PG release and attenuated persistent pain and hyperalgesia, approximately 500- 1000 more potently when compared with systemic administration suggesting a central site of action. Cyclooxygenase (COX), the enzyme for PG synthesis, is present in the spinal dorsal horn where the nociceptive C-fibers terminate. Furthermore, i.t. PGE₂ induces hyperalgesia and allodynia in conscious mice. All these observations support the hypothesis that PGs are involved in C-fiber mediated spinal sensitization processes underlying hyperalgesia and allodynia. Tactile stimulation (Aβ-fiber input) induces prominent, well-defined allodynia after i.t. bicuculline (BIC) in the rat. However, the mechanism of allodynia is unclear. The objective of the present study was to determine whether the low threshold mechanoreceptive (Aβ) primary afferent fibers activate a similar prostanoid-sensitizing mechanism in the rat spinal cord in allodynia. Male Sprague Dawley rats (325-400g) 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 bicuculline (0.1 µg in 0.1 µl) 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 (HD) (brushing the hair with a cotton-tipped applicator) in the presence, but not absence of bicuculline, 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. Bicuculline-allodynia was dose-dependent, yielding ED50 values (95% Cl) of 0.055 mg (0.035-0.085) for MAP; 0.075 mg (0.048-0.118) for HR and 0.097 mg (0.078-0.122) for MR. Allodynia was sustained for up to 2 h with repeated bicuculline doses without any detectable change in the location or area of peripheral sensitization. Pretreatment with either the EP-receptor antagonist, SC-51322, the cyclooxygenase (COX)-2 selective inhibitor, NS-398, or the NMDA-receptor antagonist, AP-7, inhibited bicuculline-allodynia in a dose-dependent manner. Innocuous tactile stimulation in the presence of i.t. PGE₂ induced nociceptive-like behavioural responses (allodynia) in conscious rats. These allodynic responses were attenuated by SC-51322, or AP-7. Bicuculline, given i.t. 5 min before PGE₂, enhanced PGE₂-induced allodynia and shifted the PGE₂ dose-response curve to the left. The spontaneous behavioural response after i.t. PGE₂ was also enhanced by bicuculline, but to a much less extent. The present results demonstrate: a) the utility of topical drug delivery for inducing highly localized and sustained allodynia in the lightly-anaesthetized rat; b) that PGs, synthesized by constitutive COX-2 in the spinal cord in response to NMDA-dependent afferent input, contribute to the abnormal processing of tactile input via spinal EP-receptors; c) i.t PGE₂ induces allodynia in conscious rats which is mediated by EP and NMDA receptors, and is potentiated by pretreatment with i.t. bicuculline. These results suggest that low threshold afferent input acquires access to a PG-sensitizing process during bicuculline-disinhibition in the rat.

Item Type: Thesis (Masters)
URI: http://research.library.mun.ca/id/eprint/1430
Item ID: 1430
Additional Information: Bibliography: leaves 89-113
Department(s): Medicine, Faculty of
Date: 2001
Date Type: Submission
Library of Congress Subject Heading: Allodynia; Prostaglandins
Medical Subject Heading: Pain; Receptors, Prostaglandin

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