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Research ArticleNEUROPHARMACOLOGY

Coadministration of Intrathecal Strychnine and Bicuculline Effects Synergistic Allodynia in the Rat: An Isobolographic Analysis

Christopher W. Loomis, Hemal Khandwala, Geraldine Osmond and Michael P. Hefferan
Journal of Pharmacology and Experimental Therapeutics March 2001, 296 (3) 756-761;
Christopher W. Loomis
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Hemal Khandwala
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Geraldine Osmond
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Michael P. Hefferan
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Abstract

Tactile allodynia can be modeled in experimental animals by acutely blocking spinal glycine or GABAA receptors with intrathecal (i.t.) strychnine (STR) or bicuculline (BIC), respectively. To test the hypothesis that glycine and GABA effect cooperative (supra-additive) inhibition of touch-evoked responses in the spinal cord, male Sprague-Dawley rats, fitted with chronic i.t. catheters, were used. Following i.t. STR, BIC, or STR + BIC, hair deflection evoked cardiovascular (increased blood pressure and heart rate), motor (scratching, kicking and rippling of the affected dermatomes), and cortical encephalographic responses. Hair deflection was without effect in i.t. saline-treated rats. Isobolographic analysis of STR (ED50 = 25.1–36.9 μg), BIC (ED50 = 0.5–0.6 μg), and BIC:STR combination (ED50 = 0.026–0.034:2.6–3.4 μg) dose-response curves confirmed a supra-additive interaction between BIC and STR in this model. BIC-allodynia was reproduced by i.t. picrotoxin. Pretreatment with i.t. scopolamine, or i.t. muscarine had no effect. STR-allodynia was dose dependently inhibited by i.t. muscimol but not baclofen. The results of this study indicate that 1) glycine and GABA effect cooperative inhibition of low-threshold mechanical input in the spinal cord of the rat; and 2) BIC-allodynia arises from the blockade of GABAAreceptors and is unrelated to any secondary anticholinesterase activity. The allodynic state induced by the blockade of glycine or GABA receptors is clearly exacerbated by the removal of both inhibitory systems. Their combined loss after neural injury may explain the exaggerated sensitivity to and subsequent miscoding of tactile information as pain.

Footnotes

  • Send reprint requests to: Dr. C. W. Loomis, School of Pharmacy, Health Sciences Center, Memorial University of Newfoundland, St. John's, Newfoundland, Canada, A1B 3V6. E-mail:cwloomis{at}morgan.ucs.mun.ca

  • This research was supported by an operating grant from the Medical Research Council (MRC) of Canada. H.K. and G.O. were the recipients of Pharmaceutical Manufacturers Association of Canada (PMAC)-Health Research Foundation/MRC Scholarships.

  • Abbreviations:
    GABA
    γ-aminobutyric acid
    i.t.
    intrathecal
    BIC
    bicuculline
    STR
    strychnine
    IPSP
    inhibitory postsynaptic potential
    EEG
    electroencephalograph
    HD
    hair deflection
    MAP
    mean arterial pressure
    HR
    heart rate
    CI
    confidence interval
    BP
    blood pressure
    AP-5
    2-amino-5-phosphonopentanoic acid
    l-AP4
    l(+)-2-amino-4-phosphonobutyric acid
    l-AP3
    l(+)-2-amino-3-phosphonopropionic acid
    • Received July 19, 2000.
    • Accepted November 9, 2000.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 296 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 296, Issue 3
1 Mar 2001
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Research ArticleNEUROPHARMACOLOGY

Coadministration of Intrathecal Strychnine and Bicuculline Effects Synergistic Allodynia in the Rat: An Isobolographic Analysis

Christopher W. Loomis, Hemal Khandwala, Geraldine Osmond and Michael P. Hefferan
Journal of Pharmacology and Experimental Therapeutics March 1, 2001, 296 (3) 756-761;

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Research ArticleNEUROPHARMACOLOGY

Coadministration of Intrathecal Strychnine and Bicuculline Effects Synergistic Allodynia in the Rat: An Isobolographic Analysis

Christopher W. Loomis, Hemal Khandwala, Geraldine Osmond and Michael P. Hefferan
Journal of Pharmacology and Experimental Therapeutics March 1, 2001, 296 (3) 756-761;
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