Antinociceptive potentiation and attenuation of tolerance by intrathecal co-infusion of magnesium sulfate and morphine in rats.
N-methyl-D-aspartate (NMDA) antagonists, such as MK801, delay the development of morphine tolerance. Magnesium, a noncompetitive NMDA antagonist, reduces postoperative morphine requirements. The present study was designed to evaluate the effects of intrathecal co-administration of magnesium sulfate with morphine on antinociceptive potentiation, tolerance, and naloxone-induced withdrawal signs. Magnesium sulfate (40-60 microg/h) co-administration for 7 days, similar to MK801 (10 nmol/h), prevented the decline in antinociceptive response compared with morphine (20 nmol/h). Magnesium sulfate (60 microg/h) produced no antinociception, but co-infused with morphine (1 nmol/h), it resulted in potentiated antinociception compared with morphine throughout the 7-day period. Probe morphine doses after 7-day infusions demonstrated a significantly greater 50% effective dose value for morphine 1 nmol/h (109.7 nmol) compared with saline (10.9 nmol), magnesium sulfate 60 microg/h (10.9 nmol), and magnesium sulfate 60 microg/h plus morphine 1 nmol/h (11.2 nmol), which indicates that magnesium had delayed morphine tolerance. Morphine withdrawal signs after naloxone administration were not altered by the co-infusion of magnesium sulfate. Cerebrospinal fluid magnesium levels after intrathecal magnesium sulfate (60 microg/h) for 2 days increased from 17.0 +/- 1.0 microg/mL to 41.4 +/- 23.6 microg/mL, although serum levels were unchanged. This study demonstrates antinociceptive potentiation and delay in the development of morphine tolerance by the intrathecal coinfusion of magnesium sulfate and morphine in the rat.


CONCLUSIONS
The addition of magnesium sulfate, an N-methyl-D-aspartate antagonist, to morphine in an intrathecal infusion provided better analgesia than morphine alone in normal rats. These results suggest that intrathecal administration of magnesium sulfate may be a useful adjunct to spinal morphine analgesia.
McCarthy
R J
RJ
Department of Anesthesiology, Rush Medical College at Rush-Presbyterian-St. Luke's Medical Center, Chicago, Illinois 60612, USA. rmccarth@rpslmc.edu
Kroin
J S
JS
Tuman
K J
KJ
Penn
R D
RD
Ivankovich
A D
AD
D000698:Analgesia; D000700:Analgesics / Q000008:administration & dosage / Q000097:blood / Q000134:cerebrospinal fluid / Q000494:pharmacology*; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000097:blood / Q000134:cerebrospinal fluid / Q000494:pharmacology*; D000818:Animals; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004347:Drug Interactions; D004357:Drug Synergism; D004361:Drug Tolerance; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage / Q000097:blood / Q000134:cerebrospinal fluid / Q000494:pharmacology*; D007278:Injections, Spinal; D008278:Magnesium Sulfate / Q000008:administration & dosage / Q000097:blood / Q000134:cerebrospinal fluid / Q000494:pharmacology*; D008297:Male; D009020:Morphine / Q000008:administration & dosage / Q000097:blood / Q000134:cerebrospinal fluid / Q000494:pharmacology*; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000187:drug effects; D013375:Substance Withdrawal Syndrome / Q000503:physiopathology; D013997:Time Factors
D000700:Analgesics; D000701:Analgesics, Opioid; D004338:Drug Combinations; D018691:Excitatory Amino Acid Antagonists; D009292:Narcotic Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D009270:Naloxone; D016291:Dizocilpine Maleate; D008278:Magnesium Sulfate; D009020:Morphine