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Methadone is a long-acting opioid used in the treatment of various pain states and substitution therapy in heroin addiction. Extensive behavioral characterization has been carried out using the racemate, but limited investigation has been performed with the individual isomers. The L-isomer is a potent opioid agonist, whereas the D-isomer has weak µ-opioid activity and has also been shown to possess N-methyl-D-aspartate antagonist properties in vitro. The acute antinociceptive effects of the isomers were evaluated in rats using a warm-water, tail-withdrawal procedure at two stimulus intensities (50° and 55°C). Increasing dose ratios of D-methadone to L-methadone were administered chronically to determine the ability of the D-isomer to modulate antinociceptive tolerance to the L-isomer. Acutely, both L-methadone (0.1-5.6 mg/kg, subcutaneously) and D-methadone (3.0-56.0 mg/kg, subcutaneously) produced antinociception, although the efficacy of the D-isomer was limited at 55°C. These effects were dose dependently blocked by naltrexone (0.01-1.0 mg/kg, subcutaneously). Administered chronically, D-methadone (1.7-10 mg/kg, subcutaneously) dose dependently blocked tolerance development to the L-isomer (1.7 mg/kg, subcutaneously). These findings support the antinociceptive effects of the isomers being opioid receptor mediated with the L-isomer functioning as a full-efficacy agonist, whereas the D-isomer seems to have lower efficacy. The ability of nonracemic doses of the D-isomer to prevent tolerance development to the L-isomer may be attributed to partial µ-agonist activity; however, N-methyl-D-aspartate antagonist activity cannot be discounted.

Characterization of the antinociceptive effects of the individual isomers of methadone after acute and chronic administrations