(S)-(+)methadone is more immunosuppressive than the potent analgesic (R)-(-)-methadone

Abstract

Methadone is a widely used synthetic opioid which is administered as a racemic mixture of (R)-(−)- and (S)-(+)-enantiomers, with only (R)-(−)-methadone possessing μ opioid receptor agonist activity. Methadone inhibits numerous immune functions in vitro at concentrations above 10 μM in a nonstereoselective and naloxone-insensitive fashion, suggesting the presence of nonclassical opioid receptors on immune cells. No in vivo data on the effects of methadone's enantiomers on immune function are available. Therefore, the stereoselectivity of methadone's analgesia (hot plate latency) in vivo and immune suppression ex vivo (splenocyte proliferation) was investigated in groups of Balb/c mice. Significant analgesia was observed in animals that received racemic methadone (P=0.0012, 52% MPE) and (R)-(−)-methadone (P=0.0002, 70% MPE) when compared to saline-treated controls, while (S)-(+)-methadone was devoid of any such effect (−4% MPE). In vivo (R)-(−)- and racemic methadone caused significant inhibition (P<0.001, greater than −70%) of basal proliferation compared to saline control. In stark contrast to analgesia, in vivo (S)-(+)-methadone caused significantly greater inhibition of basal proliferation (P<0.001, −130%) than (R)-(−)- and racemic methadone. The immune suppression caused by methadone is not purely a classical opioid response but involves nonclassical opioid receptors located at the central level, which have yet to be characterised. Moreover, the dose at which immune suppression occurred could be achieved clinically.