S-Methadone augments R-methadone induced respiratory depression in the neonatal guinea pig

Abstract

Methadone is administered as a racemic mixture, although its analgesic and respiratory effects are attributed to R-isomer activity at the mu opioid receptor (MOP). Recently, we observed a four-fold increase in inspiratory time in 3-day-old guinea pigs following an injection of racemic methadone. We hypothesized that this effect was due to augmentation of R-methadone induced respiratory depression by the S-methadone isomer. In the current longitudinal study, we injected 3-, 7-, and 14-day-old neonatal guinea pigs with saline, R-methadone, S-methadone, or R- plus S-methadone in order to characterize the roles of the individual isomers, as well as the synergistic effects of co-administration. Using plethysmography, we measured respiratory parameters while breathing room air and during a 5% CO(2) challenge. S-Methadone alone had no respiratory effects. However, the R- plus S-methadone group showed greater respiratory depression and increased inspiratory time than the R-methadone group in the youngest animals, suggesting that the respiratory effects of R-methadone are augmented by S-methadone in early development.

Fig. 1

Time action curves for ventilatory response of neonatal guinea pigs during RA breathing and CO₂ challenge for $\stackrel{.}{\mathrm{V}}\mathrm{I}$, f_R, and V_T on days 3 (A-F), 7 (G-L), and 14 (M-R). Data presented as mean ± SE (n=6) *p<0.05, **p<0.01, ***p<0.001 vs both control groups ^†p<0.05, ^†††p<0.01, ^†††p<0.001 vs R-methadone

Fig. 2

Maximum respiratory depression in neonatal guinea pigs for V_T/T_I (A-B), T_I (C-D), and T_E (E-F) during RA breathing and CO₂ challenge. Data presented as mean ± SE (n=6) *p<0.05, **p<0.01, ***p<0.001 vs both control groups ^†p<0.05, ^††p<0.01, ^†††p<0.001 vs R-methadone ^a p<0.05 vs day 7 same treatment ^b p<0.05 vs day 14 same treatment

Fig. 3

Maximum respiratory depression for neonatal guinea pig treatment groups containing R-methadone for $\stackrel{.}{\mathrm{V}}\mathrm{I}\left(\mathrm{A}\right)$, f_R (B), and V_T (C) during CO₂ challenge and NMDA antagonism. Data presented as mean ± SE (n=6) *p<0.05, **p<0.01, ***p<0.001 vs both control groups ^†p<0.05, ^††p<0.01 vs R-methadone ^a p<0.05 vs day 7 same treatment ^b p<0.05 vs day 14 same treatment

Fig. 4

Metabolic parameters $\stackrel{.}{\mathrm{V}}{\mathrm{O}}_2\left(\mathrm{A}\right)$, $\stackrel{.}{\mathrm{V}}{\mathrm{CO}}_2\left(\mathrm{B}\right)$, $\stackrel{.}{\mathrm{V}}\mathrm{I}∕\stackrel{.}{\mathrm{V}}{\mathrm{O}}_2\left(\mathrm{C}\right)$, and $\stackrel{.}{\mathrm{V}}\mathrm{I}∕\stackrel{.}{\mathrm{V}}{\mathrm{CO}}_2\left(\mathrm{D}\right)$ for neonatal guinea pigs at the same time periods as the maximum respiratory depression during CO₂ challenge. Data presented as mean ± SE (n=6) **p<0.01, ***p<0.001 vs both control groups ^††p<0.01 vs R-methadone ^b p<0.05 vs day 14 same treatment