Abstract
This study investigated the role of γ-aminobutyric acid (GABA) and GABAA receptors in the spinal cord in the expression of pain behaviors evoked by injection of formalin in concentrations ranging from 0.25 to 2.5% in the hindpaw of the rat. Two approaches were used. The first approach compared the effect of drug treatment to saline at each concentration of formalin. The second approach examined the effect of drug treatment on the concentration-response functions of formalin, i.e., its EC50. Intrathecal (i.t.) pretreatment with 0.03 to 0.3 μg of bicuculline, a GABAA receptor antagonist, dose-dependently increased the number of flinches and weighted pain scores in the interphase and phase 2, but did not alter responses in phase 1. In the interphase, the EC50values of formalin for number of flinches or weighted pain score in bicuculline-pretreated rats were decreased to one-third or one-fourth, respectively, of their values in saline-pretreated rats. In phase 2, the EC50 values of formalin for number of flinches or weighted pain score in bicuculline-pretreated rats were similarly decreased to one-half of their value in saline-pretreated rats. These results suggest that formalin was a significantly more noxious stimulus in the presence of bicuculline. Pretreatment with the GABAA receptor agonists, muscimol (0.3 μg) or isoguvacine (10 or 30 μg i.t.), significantly decreased the number of flinches in phase 1 and phase 2, but produced only a marginal decrease in the weighted pain score at the highest doses. These findings suggest that there is little tonic activation of GABAAreceptors by GABA in the spinal cord before or immediately after the injection of formalin. However, approximately 10 min after the induction of injury by formalin, there is a release of GABA and activation of GABAA receptors in the spinal cord that 1) contributes to the period of quiescence between phase 1 and phase 2 and 2) coincidentally diminishes the magnitude of pain behaviors in phase 2, possibly by limiting the development of central sensitization in the spinal cord.
Footnotes
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Send reprint requests to: Donna L. Hammond, Ph.D., Department of Anesthesia & Critical Care, University of Chicago, 5841 South Maryland Avenue M/C 4028, Chicago, IL 60637.
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↵1 This work was supported by U.S.P.H.S. grant DE11423 from the National Institute for Dental Research (to D.L.H.).
- Abbreviations:
- GABA
- γ-aminobutyric acid
- NMDA
- N-methyl-d-aspartate
- i.t.
- intrathecal
- LTP
- long-term potentiation
- EC50
- effective concentration
- CL
- 95% confidence limit
- Received January 21, 1997.
- Accepted April 11, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
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