Lack of Effect of Intrathecally Administered N-methyl-D-aspartate Receptor Antagonists in a Rat Model for Postoperative Pain 

1998 ◽  
Vol 88 (1) ◽  
pp. 143-156 ◽  
Author(s):  
Peter K. Zahn ◽  
Timothy J. Brennan
Keyword(s):  
Nmda Receptor ◽  
Postoperative Pain ◽  
Rat Model ◽  
Intrathecal Administration ◽  
Nmda Receptor Antagonist ◽  
Nmda Receptor Antagonists ◽  
Receptor Antagonists ◽  
Mk 801 ◽  
Pain Behaviors ◽  
Plantar Incision

Background Evidence from experiments by others indicates an important role for excitatory amino acids activating spinal n-methyl-d-aspartate (NMDA) receptors in models of persistent pain. The purpose of this study was to examine the effect of intrathecal (+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cyclohepten-5,10-imine (MK-801), a noncompetitive NMDA receptor antagonist, 2-amino-5-phosphonovaleric acid (AP5), a competitive NMDA receptor antagonist, and N-G-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor, on pain behaviors in a rat model of postoperative pain. Methods Rats with intrathecal catheters were anesthetized and underwent a plantar incision. Withdrawal threshold to punctate stimulation applied adjacent to the wound, response frequency to application of a nonpunctate stimulus applied directly to the wound, and nonevoked pain behaviors were measured before and after intrathecal administration of MK-801 or AP5. The effect of intrathecal L-NAME on mechanical hyperalgesia was also examined. Results Mechanical hyperalgesia increased and was persistent after plantar incision and was not decreased by intrathecal administration of 4, 14, or 40 nmol MK-801 or 10 nmol AP5. Only the greatest dose of AP5, 30 nmol, caused a small decrease in punctate and nonpunctate hyperalgesia. Intrathecal L-NAME had no effect. Neither intrathecal MK-801 nor intrathecal AP5 affected nonevoked pain behaviors. The greatest doses caused motor deficits. Conclusions Unlike intrathecal and systemic morphine, intrathecal NMDA receptor antagonists did not modify pain behaviors in this rat model of postoperative pain. These data suggest that NMDA receptors do not play an important role in the maintenance of postoperative pain behaviors and that NMDA receptor antagonists, administered spinally by themselves during the postoperative period, will not be useful for the treatment of postoperative pain in humans.

Autoradiographic analysis of 3H-MK-801 (dizocilpine) in vivo uptake and in vitro binding after focal cerebral ischemia in the rat

1992 ◽  
Vol 76 (1) ◽  
pp. 127-133 ◽  
Author(s):  
Michael C. Wallace ◽  
Graham M. Teasdale ◽  
James McCulloch
Keyword(s):  
Nmda Receptor ◽  
Caudate Nucleus ◽  
Intravenous Administration ◽  
Nmda Receptor Antagonists ◽  
Contralateral Hemisphere ◽  
Receptor Antagonists ◽  
Isotopic Tracer ◽  
Mk 801 ◽  
Ischemic Tissue

✓ The clinical utility of N-methyl-D-aspartate (NMDA) receptor antagonists is now being assessed in ischemic brain injury in humans. The uptake and retention of NMDA receptor antagonists in ischemic tissue will influence the design of clinical trials. The effects of permanent occlusion of the middle cerebral artery, induced 15 minutes prior to isotope administration, on the uptake of 3H-MK-801 (dizocilpine) have been assessed in the rat with quantitative autoradiography. In a group of three rats at 15 minutes after the intravenous administration of 3H-MK-801, the level (mean ± standard error of the mean) of isotopic tracer in the ischemic cortex and striatum was markedly less than that in the contralateral hemisphere (ipsilateral vs. contralateral caudate nucleus: 22 ± 4 vs. 84 ± 11 pmol/gm, p < 0.01). In contrast, in a group of five rats at 60 minutes after the intravenous administration of 3H-MK-801, the level of isotopic tracer in the ischemic cortex and striatum was greater than that in the contralateral hemisphere (ipsilateral vs. contralateral caudate nucleus: 52 ± 8 vs. 32 ± 4 pmol/gm, p < 0.05). There were no significant alterations in the specific binding of 3H-MK-801 in vitro in ischemic tissue at equivalent times. The early uptake of 3H-MK-801 into the central nervous system is dominated by the level of cerebral blood flow, whereas at later times after administration enhancement of MK-801 binding by elevated extracellular glutamate concentrations appears to be more important in determining the level of the drug in ischemic tissue.

Effect of Pretreatment with Intrathecal Excitatory Amino Acid Receptor Antagonists on the Development of Pain Behavior Caused by Plantar Incision

2000 ◽  
Vol 93 (2) ◽  
pp. 489-496 ◽  
Author(s):  
Esther M. Pogatzki ◽  
Peter K. Zahn ◽  
Timothy J. Brennan
Keyword(s):  
Amino Acid ◽  
Nmda Receptor ◽  
Excitatory Amino Acid ◽  
Pain Behavior ◽  
Receptor Antagonists ◽  
Excitatory Amino Acid Receptor ◽  
Mk 801 ◽  
Acid Receptor ◽  
Group I ◽  
Plantar Incision

Background Drugs that block spinal excitatory amino acid receptor activation may prevent pain after surgery. The authors previously studied the effect of excitatory amino acid receptor antagonists after incision. In the present study, we examined the role of N-methyl-d-aspartate (NMDA), non-NMDA, and metabotropic glutamate receptors (mGluRs) on the development of pain behavior after plantar incision. Methods Rats with lumbar intrathecal catheters were anesthetized with halothane. Fifteen minutes before an incision was made, drug [40 nmol MK-801; 20 nmol NBQX; or 200 nmol (+)-MCPG] or vehicle was injected intrathecally followed by an infusion of the same drug for 75 min. Withdrawal thresholds to calibrated von Frey filaments applied adjacent to the wound and response frequencies to a blunt mechanical stimulus applied directly to the wound were measured before incision and 1, 2, 4, and 6 h after incision and then once daily for 6 days. Results Preincision treatments with antagonists against the NMDA (MK-801) and group I and II metabotropic receptors [(+)-MCPG] did not inhibit the development of mechanical hyperalgesia caused by incision. Preincision treatment with the non-NMDA receptor antagonist NBQX increased withdrawal thresholds at 1 and 2 h and on postoperative day 1 compared with the vehicle group; response frequencies were reduced 1 and 2 h after incision and on postoperative day 2 (P &lt; 0.05). In an additional group, postincision treatment with NBQX was similar to preincision treatment. Conclusion Spinal NMDA and mGluR antagonists may not be useful for preventing postsurgical pain. Spinal non-NMDA receptor antagonists reduced pain behaviors, but a preventive effect using preincision treatment was not apparent.

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