Coadministration of intrathecal strychnine and bicuculline effects synergistic allodynia in the rat: an isobolographic analysis.
Tactile allodynia can be modeled in experimental animals by acutely blocking spinal glycine or GABA(A) 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 (ED(50) = 25.1-36.9 microg), BIC (ED(50) = 0.5-0.6 microg), and BIC:STR combination (ED(50) = 0.026-0.034:2.6-3.4 microg) 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 GABA(A) receptors 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.
Loomis
C W
CW
School of Pharmacy, Faculty of Medicine, Memorial University of Newfoundland St. John's, Newfoundland, Canada. cwloomis@morgan.ucs.mun.ca
Khandwala
H
H
Osmond
G
G
Hefferan
M P
MP
D000704:Analysis of Variance; D000818:Animals; D001640:Bicuculline / Q000633:toxicity*; D003292:Convulsants / Q000633:toxicity; D004357:Drug Synergism; D007278:Injections, Spinal; D008297:Male; D010146:Pain / Q000139:chemically induced*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000502:physiology; D013331:Strychnine / Q000633:toxicity*
D003292:Convulsants; D011963:Receptors, GABA-A; D013331:Strychnine; D001640:Bicuculline