title: NMDA receptor antagonist treatment at the time of nerve injury prevents injury-induced changes in spinal NR1 and NR2B subunit expression and increases the sensitivity of residual pain behaviours to subsequently administered NMDA receptor antagonists.
abstract: Spinal NMDA receptors (NMDA R) are important in neuropathic sensitisation and acute administration of antagonists can provide temporary attenuation of sensitisation. If establishment of the chronic pain state could be prevented by brief administration of such agents at or around the time of nerve injury (pre-emptive analgesia) it might be possible to avoid many of the unacceptable side effects associated with repeated administration of these or other antagonists. Several reports describe aspects of effective pre-emptive analgesia from NMDA R antagonists in animal models of neuropathic pain. The first aim of the present study was to make a direct comparison of changes in mechanical allodynia, cold allodynia and thermal hyperalgesia following nerve injury, demonstrating their increasing degree of susceptibility to pre-emptive NMDA R antagonist treatment. Secondly, we used immunoblotting and immunohistochemistry to investigate the effects of nerve injury on NMDA receptor subunit expression, revealing increased expression of NR2B, but not NR2A and reduced NR1 in the superficial dorsal horn. These changes were attenuated following NMDA receptor antagonist pre-treatment. Thirdly, we investigated the pharmacological properties of residual mechanical allodynia and cold allodynia that remained after pre-emptive treatment and revealed a greater sensitivity to NMDA R antagonists. These findings indicate that in addition to a marked suppression of thermal hyperalgesia and cold allodynia, pre-emptive treatment with NMDA R antagonist causes a lasting change in spinal NMDA R complexes such that remaining mechanical allodynia should be more effectively targeted by NMDA R antagonists.
authors.affiliation: Centre for Neuroscience Research, Division of Veterinary Biomedical Sciences, The Royal (Dick) School of Veterinary Studies, The University of Edinburgh, Summerhall, Edinburgh EH9 1QH, UK Department of Anaesthesia, Critical Care & Pain Medicine, Western General Hospital, Crewe Rd, Edinburgh EH4 2XU, UK Centre for Integrative Physiology (Membrane Biology Group), School of Biomedical and Clinical Laboratory Sciences, University of Edinburgh EH8 9XD, UK.
authors.forename: John A
authors.initials: JA
authors.lastname: Wilson
authors.forename: Emer M
authors.initials: EM
authors.lastname: Garry
authors.forename: Heather A
authors.initials: HA
authors.lastname: Anderson
authors.forename: Roberta
authors.initials: R
authors.lastname: Rosie
authors.forename: Lesley A
authors.initials: LA
authors.lastname: Colvin
authors.forename: Rory
authors.initials: R
authors.lastname: Mitchell
authors.forename: Susan M
authors.initials: SM
authors.lastname: Fleetwood-Walker
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal; D015153:Blotting, Western / Q000379:methods; D004195:Disease Models, Animal; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage* / Q000627:therapeutic use; D007839:Functional Laterality; D005786:Gene Expression Regulation / Q000187:drug effects; D008297:Male; D010146:Pain / Q000150:complications / Q000517:prevention & control*; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D011930:Reaction Time / Q000187:drug effects; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013116:Spinal Cord / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D013997:Time Factors; D020196:Trauma, Nervous System / Q000150:complications / Q000188:drug therapy
chemical_list: D018691:Excitatory Amino Acid Antagonists; C409466:NR1 NMDA receptor; C121001:NR2B NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate