Previous studies suggested that combining
N-methyl-d-aspartate (
NMDA) receptor antagonists with either mu-
opioid agonist
morphine or alpha2-adrenoreceptor agonist
clonidine results in the significant synergistic enhancement of
analgesic activity in the animal models of acute and
neuropathic pain. When given alone,
NMDA receptor antagonists,
morphine and
clonidine are capable of attenuating
tactile allodynia associated with chronic nerve injury. The present study aimed to assess anti-allodynic effects of these compounds and to test additivity of these interactions using isobolographic analysis. Adult male Wistar rats with unilateral loose
ligation of sciatic nerve developed significant
tactile allodynia (between-paw difference of about 18-20 g). In separate groups of animals, dose-dependent anti-allodynic activity was confirmed for
memantine (1.8-17.8 mg/kg),
neramexane (1.8-17.8 mg/kg),
morphine (1-10 mg/kg) and
clonidine (0.01-0.1 mg/kg). In a subsequent series of experiments,
memantine (or
neramexane) and
morphine (or
clonidine) were co-administered at the fixed equi-effective dose ratios (six dose levels per
drug combination). None of the tested combinations produced supra-additive, synergistic effects. In fact, memantine+clonidine, neramexane+clonidine and morphine+neramexane were producing simple additive effects, while morphine+memantine was characterized as the infra-additive combination. Thus, despite expectations based on previous studies,
NMDA receptor channel blockers,
memantine and
neramexane, produce no synergistic interactions with either
morphine or
clonidine when administered acutely to rats with nerve injury-induced
tactile allodynia.