[show abstract][hide abstract] ABSTRACT: 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.
[show abstract][hide abstract] ABSTRACT: Substance abuse and addiction are well recognized public health concerns, with 2 NIH institutes (the National Institute on Drug Abuse and the National Institute on Alcohol Abuse and Alcoholism) specifically targeting this societal problem. As such, this is an important area of research for which animal experiments play a critical role. This overview presents the importance of substance abuse and addiction in society; reviews the development and refinement of animal models that address crucial areas of biology, pathophysiology, clinical treatments, and drug screening for abuse liability; and discusses some of the unique veterinary, husbandry, and IACUC challenges associated with these models.
Comparative medicine 06/2010; 60(3):177-88. · 1.12 Impact Factor