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 deve lopment of morphine tolerance. Magnesium, a noncompetitive NMDA antago nist, reduces postoperative morphine requirements. The present study w as designed to evaluate the effects of intrathecal co-administration o f magnesium sulfate with morphine on antinociceptive potentiation, tol erance, and naloxone-induced withdrawal signs. Magnesium sulfate (40-6 0 mu g/h) co-administration for 7 days, similar to MK801 (10 nmol/h), prevented the decline in antinociceptive response compared with morphi ne (20 nmol/h). Magnesium sulfate (60 mu g/h) produced no antinocicept ion, but co-infused with morphine (1 nmol/h), it resulted in potentiat ed antinociception compared with morphine throughout the 7-day period. Probe morphine doses after 7-day infusions demonstrated a significant ly greater 50% effective dose value for morphine 1 nmol/h (109.7 nmol) compared with saline (10.9 nmol), magnesium sulfate 60 mu g/h (10.9 n mol), and magnesium sulfate 60 mu g/h plus morphine 1 nmol/h (11.2 nmo l), which indicates that magnesium had delayed morphine tolerance. Mor phine withdrawal signs after naloxone administration were not altered by the co-infusion of magnesium sulfate. Cerebrospinal fluid magnesium levels after intrathecal magnesium sulfate (60 mu g/h) for 2 days inc reased from 17.0 +/- 1.0 mu g/mL, to 41.4 +/- 23.6 mu g/mL, although s erum levels were unchanged. This study demonstrates antinociceptive po tentiation and delay in the development of morphine tolerance by the i ntrathecal coinfusion of magnesium sulfate and morphine in the rat. Im plications: The addition of magnesium sulfate, an N-methyl-D-aspartate antagonist, to morphine in an intrathecal infusion provided better an algesia than morphine alone in normal rats. These results suggest that intrathecal administration of magnesium sulfate may be a useful adjun ct to spinal morphine analgesia.