NMDA RECEPTOR ANTAGONISTS ATTENUATE TOLERANCE INDUCED BY MORPHINE AND NERVE LIGATION IN MICE

The effect of NMDA (N-methyl-D-aspartate) receptor antagonists on tolerance to morphine antinociception was investigated in mice. Daily subcutaneous administration of 50 mg/kg of morphine hydrochloride for three days induced tolerance to different (3,6 and 9 mg/kg) test doses of morphine. The tolerance obtained was decreased by pretreatment of animals with single or repeated doses of competitive NMDA receptor antagonists D-( -)-2-amino-5-phosphonovaleric acid (DAP5 0.1-0.3 mg/kg) and D-(-)-2-amino-7-phosphonoheptanoic acid (DAP7 0.1-0.3 mg/kg). Tolerance to morphine response was also obtained 7, 14, 21 and 30 days after unilateral sciatic nerve ligation. Single or repeated doses (0.2 mg/kg) of DAP5 or DAP7 increased the antinociceptive response induced by morphine (9 mg/kg) in the nerve ligated animals. We report that these agents attenuate the development of morphine tolerance, and increase the antinociceptive effect of morphine on sciatic neuropathic pain in mice.