Abstract
Neuropathic pain remains a significant clinical problem. Current understanding implicates the spinal cord dorsal horn N-methyl-d-aspartate (NMDA) receptor apparatus in its pathogenesis. Previous reports have described NMDA antagonist reduction of nerve injury-induced thermal hyperalgesia and formalin injection-related electrical activity. We examined a panel of spinally administered NMDA antagonists in two models: allodynia evoked by tight ligation of the fifth and sixth lumbar spinal nerves (a model of chronic nerve injury pain), and the formalin paw test (a model wherein pretreatment with drug may preempt the development of a pain state). A wide range of efficacies was observed. In the nerve injury model, order of efficacy (expressed as percent of maximum possible effect ± S.E.), at the maximum dose not yielding motor impairment, was memantine (96 ± 5%) = AP5 (91 ± 7%) > dextrorphan (64 ± 11%) = dextromethorphan (65 ± 22%) > MK801 (34 ± 8%) > ketamine (18 ± 6%). For the formalin test, the order of efficacy was AP5 (86 ± 9%) > memantine (74 ± 5%) ≥ MK801 (67 ± 16%) > dextrorphan (47 ± 16%) > dextromethorphan (31 ± 12%) > ketamine (17 ± 15%). In the nerve injury model, no supraspinal action was seen after intracerebroventricular injections of dextromethorphan and ketamine. NMDA antagonists by the spinal route appear to be useful therapeutic agents for chemically induced facilitated pain as well as nerve injury induced tactile allodynia. It is not known what accounts for the wide range of efficacies.
Footnotes
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Send reprint requests to: Dr. Sandra R. Chaplan, Anesthesiology Research Laboratory, 0818, 9500 Gilman Drive, University of California, La Jolla, CA 92093-0818.
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↵1 This work was supported by NIH Grants DA02110 (T.L.Y.) and THNS T-32-NS-07407 and the RSD Foundation (S.R.C.). Portions of this work were presented at the following meetings: CSA 4/93, IASP 8/93, ASA 10/93, SASP 3/94).
- Abbreviations:
- % MPE
- percent of maximum possible effect
- ANOVA
- analysis of variance
- AP3
- ±-2-amino-3-phosphonopropionic acid
- AP5
- ±-2-amino-5 phosphonopentanoic acid
- Ca++
- calcium
- CI
- confidence interval
- DNQX
- 6,7,dinitroquinoxaline-2,3-dione
- ICV
- intracerebroventricular
- IT
- intrathecal
- L2 (3
- 4,5,6), second (third, fourth, fifth, sixth) lumbar nerve(s)
- MD
- motor dysfunction
- Mg++
- magnesium
- mGluR
- metabotropic glutamate receptor
- MK801
- dizocilpine maleate
- MPE
- maximum possible drug effect
- NMDA
- N-methyl d-aspartate
- PE
- polyethylene
- S1 (2)
- first (second) sacral nerve
- TI
- therapeutic index
- Received February 27, 1996.
- Accepted October 21, 1996.
- The American Society for Pharmacology and Experimental Therapeutics
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