Peripherally acting NMDA receptor/glycine B site receptor antagonists inhibit morphine tolerance

Abstract

The present study focused on the role of peripheral ionotropic N-methyl- d-aspartate (NMDA) receptors in the development of tolerance to morphine-induced antinociception. An initial experiment revealed that NMDA channel blocker memantine, and NMDA receptor/glycine B site antagonist MRZ 2/576 inhibited maximal electroshock-induced convulsions (MES) in female NMR mice with respective potency of 5.93 and 20.8 mg/kg, while other NMDA receptor/glycine B site antagonists MRZ 2/596 and MDL 105,519 were ineffective, supporting lack of CNS activity of the latter two agents. This observation was also supported by blood–brain barrier experiments in vitro. In male Swiss mice, morphine (10 mg/kg) given for 6 days twice a day (b.i.d.) produced tolerance to its antinociceptive effects in the tail-flick test. The NMDA receptor/glycine B site antagonists, MRZ 2/576 at 0.03, 0.1, 0.3 mg/kg and MRZ 2/596 at 0.1, 0.3, 3 and 10 mg/kg attenuated the development of morphine tolerance. Similarly, in male C57/Bl mice, morphine (10 mg/kg) given for 6 days b.i.d. produced tolerance to its antinociceptive effects in the tail-flick test. Like in Swiss mice, in C57/Bl mice morphine tolerance was attenuated by both MRZ 2/576 and MRZ 2/596. Another NMDA receptor/glycine B site receptor antagonist, MDL 105,519 (that very weakly penetrates to the central nervous system) also inhibited morphine tolerance at the dose of 1 but not 0.1 mg/kg. Moreover, both naloxone hydrochloride (5 and 50 mg/kg) and centrally inactive naloxone methiodide (50 mg/kg) inhibited morphine tolerance suggesting the involvement of peripheral opioid receptors in this phenomenon. The present data suggest that blockade of NMDA receptor/glycine B sites in the periphery may attenuate tolerance to the antinociceptive effects of morphine.