Vol. 281, Issue 3, 1219-1225, 1997

Spinal Infusion of N-methyl-D-aspartate Antagonist MK801 Induces Hypersensitivity to the Spinal Alpha-2 Agonist ST91 in the Rat¹

Stuart A. Dunbar and Tony L. Yaksh

Department of Anesthesiology, University of California, San Diego, LaJolla, California

MK801 (MK), an N-methyl-D-aspartate (NMDA) receptor antagonist, attenuates tolerance to spinal opioids. Whether this applies to other G-protein-coupled receptor systems is unknown. This study examines the effects of continuous spinal MK on tolerance to the antinociceptive effect of continuous spinal infusion of the alpha-2 agonist ST91 (ST). Intrathecal (i.t.) infusion pumps were implanted in rats which delivered for 7 days: saline (1 µl/h); ST (40 nmol/µl/h); MK (10 nmol/µl/h) + ST (40 nmol/µl/h); or MK (10 nmol/µl/h). Antinociception was measured daily on the hot plate. On day 8, groups received i.t. boluses of ST to generate dose-response curves. A separate ST-infused group received MK (10 nmol i.t.) on day 7. Each group received ST (40 nmol i.t.) 7 days after discontinuation of infusion. Co-infusion of MK with ST resulted in attenuation of the right shift in dose response seen in ST-infused rats and a small preservation of effect on daily testing. However, MK-infused rats showed a significant left shift in ST dose response. Acutely administered, MK did not restore ST sensitivity. One week after cessation of infusion, ST and ST + MK groups showed shorter duration of effect after i.t. ST bolus than controls. In conclusion, chronic spinal MK partially attenuates loss of sensitivity to chronic spinal ST. This supports the hypothesis that opioid- and adrenoceptor-induced tolerances are similarly modulated by the NMDA receptor. However, the increased sensitivity induced by MK alone suggests that NMDA receptor antagonism may not prevent the development of tolerance itself but may alter the expression of tolerance by inducing sensitivity via other alterations in cellular function.