EFFICACY OF SPINAL NMDA RECEPTOR ANTAGONISM IN FORMALIN HYPERALGESIA AND NERVE INJURY EVOKED ALLODYNIA IN THE RAT

Neuropathic pain remains a significant clinical problem. Current under standing implicates the spinal cord dorsal horn N-methyl-d-aspartate ( NMDA) receptor apparatus in its pathogenesis. Previous reports have de scribed NMDA antagonist reduction of nerve injury-induced thermal hype ralgesia and formalin injection-related electrical activity. We examin ed a panel of spinally administered NMDA antagonists in two models: al lodynia evoked by tight ligation of the fifth and sixth lumbar spinal nerves (a model of chronic nerve injury pain), and the formalin paw te st (a model wherein pretreatment with drug may preempt the development of a pain state). A wide range of efficacies was observed. In the ner ve injury model, order of efficacy (expressed as percent of maximum po ssible effect +/- S.E.), at the maximum dose not yielding motor impair ment, 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%) greater than or equal to MK801 (67 +/- 16%) > dextrorphan (47 +/- 16%)> dextromethorphan (31 +/- 12%) > keta mine (17 +/- 15%). In the nerve injury model, no supraspinal action wa s seen after intracerebroventricular injections of dextromethorphan an d ketamine, NMDA antagonists by the spinal route appear to be useful t herapeutic agents for chemically induced facilitated pain as well as n erve injury induced tactile allodynia. It is not known what accounts f or the wide range of efficacies.