The effect of the AMPA/kainate receptor antagonist LY293558 in a rat model of postoperative pain.
Non-N-methyl-D-aspartate (non-NMDA) glutamate receptor antagonists modify multiple pain transmission pathways and are of particular interest in analgesic development because of their capacity to interfere with evoked pain. Evoked pain is a problem for postoperative patients and is characteristic of the plantar incision model for postoperative pain. The purpose of this study was to assess the efficacy of a non-NMDA receptor antagonist LY293558 on mechanical hyperalgesia after plantar incision in the rat. Parenteral, intrathecal, or intraplantar administration of LY293558 was tested against the mechanical hyperalgesia that characterizes the model. Sprague-Dawley rats were assigned to 1 of 3 groups. LY293558 or vehicle was administered intraperitoneally, intrathecally, or intraplantarly. The hind paw withdrawal threshold to punctate stimulation by using von Frey filaments and response frequency to a nonpunctate stimulus directly to the wound were measured. Motor tests after administration of LY293558 were also examined in rats that did not undergo incision. The greatest dose of parenterally administered LY293558 (34 micromol/kg) decreased the responses to mechanical stimuli after plantar incision. Rotorod performance was decreased at these same times. Intrathecal injection of LY293558 (0.5 and 2.0 nmol) produced inhibition of mechanical sensitivity and produced lower extremity motor side effects. Repeated intrathecal administration produced sustained anesthesia for 24 hours but had no analgesic effect the next day. Local administration did not decrease response after incision. LY293558 was most effective for evoked pain when administered intrathecally.


CONCLUSIONS
Control of evoked pain after surgery is inadequate but is linked to perioperative outcome. These data suggest that non-NMDA receptor antagonists like LY293558 will be most effective for evoked pain in postoperative patients if administered spinally.
Lee
Hae-Jin
HJ
Department of Anesthesia, University of Iowa, Iowa City, 52242-1079, USA.
Pogatzki-Zahn
Esther M
EM
Brennan
Timothy J
TJ
D000344:Afferent Pathways / Q000187:drug effects / Q000378:metabolism; D000700:Analgesics / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D002264:Carboxylic Acids / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004333:Drug Administration Routes; D018691:Excitatory Amino Acid Antagonists / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D018698:Glutamic Acid / Q000378:metabolism; D006930:Hyperalgesia / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D007274:Injections, Intraperitoneal; D007278:Injections, Spinal; D007279:Injections, Subcutaneous; D007546:Isoquinolines / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D009619:Nociceptors / Q000187:drug effects* / Q000378:metabolism; D010147:Pain Measurement / Q000187:drug effects; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology; D010149:Postoperative Pain / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D010812:Physical Stimulation; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000187:drug effects* / Q000378:metabolism; D013777:Tetrazoles / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D016896:Treatment Outcome
D000700:Analgesics; D002264:Carboxylic Acids; D018691:Excitatory Amino Acid Antagonists; D007546:Isoquinolines; D018091:Receptors, AMPA; D013777:Tetrazoles; D018698:Glutamic Acid; C082309:tezampanel