Levomethadone is a full µ-opioid
agonist.[SUP][
citation needed][/SUP]
Dextromethadone does not affect opioid receptors but binds to the
glutamatergic NMDA (N-methyl-D-aspartate) receptor, and thus acts as a
receptor antagonist against
glutamate. Methadone has been shown to reduce neuropathic pain in rat models, primarily through NMDA antagonism. Glutamate is the primary excitatory
neurotransmitter in the
CNS. NMDA receptors have a very important role in modulating long term excitation and memory formation. NMDA antagonists such as
dextromethorphan (DXM),
ketamine (a dissociative anaesthetic, also M.O.A+.),
tiletamine (a veterinary anaesthetic) and
ibogaine (from the African tree
Tabernanthe iboga, also M.O.A+.) are being studied for their role in decreasing the development of tolerance to opioids and as possible for eliminating addiction/tolerance/withdrawal, possibly by disrupting memory circuitry. Acting as an NMDA antagonist may be one mechanism by which methadone decreases craving for opioids and tolerance, and has been proposed as a possible mechanism for its distinguished efficacy regarding the treatment of neuropathic pain. The
dextrorotary form (
d-methadone) acts as an NMDA antagonist and is devoid of opioid activity: it has been shown to produce analgesia in experimental models of chronic pain. Methadone also acted as a potent,
noncompetitive α[SUB]3[/SUB]β[SUB]4[/SUB] neuronal
nicotinic acetylcholine receptor antagonist in rat receptors, expressed in human embryonic kidney cell lines.[SUP]
[46]