Enhanced analgesic potency and reduced tolerance of morphine in 129/SvEv mice: evidence for a deficiency in GM1 ganglioside-regulated excitatory opioid receptor functions

Abstract

A recent study reported that chronic morphine treatment of the 129/SvEv strain of mice did not result in the usual development of tolerance observed in most other mouse strains. The authors' analyses suggested that the anomalous lack of tolerance in 129/SvEv mice might be due to a defect in NMDA receptor functions. However, our previous studies suggested that cellular signs of tolerance and dependence in chronic morphine-treated dorsal root ganglion neurons in culture are due to sustained activation of supersensitized excitatory Gs-coupled, GM1 ganglioside-regulated, opioid receptor functions. We decided, therefore, to investigate whether 129/SvEv mice might be selectively deficient in excitatory, but not inhibitory, opioid receptor functions. Using hot-water-immersion tail-flick antinociceptive assays, we observed a much lower degree of tolerance in 129/SvEv mice after treatment with daily injections of 3 mg/kg morphine (s.c.), whereas similar treatment of Swiss–Webster (SW) mice showed progressive development of marked tolerance. Interestingly, acute injections of 0.1–0.3 mg/kg morphine in naive 129/SvEv mice elicited unexpectedly large antinociceptive effects comparable in magnitude, and lasting for many hours longer, than observed with >10-fold higher doses in SW mice. Furthermore, cotreatment of 129/SvEv mice with morphine plus a low dose of naltrexone (ca. 0.1 μg/kg) that markedly enhances and prolongs morphine's antinociceptive effects in SW mice did not enhance, and often attenuated, antinociception in 129/SvEv mice. These comparative data suggest that 129/SvEv mice may be deficient in excitatory opioid receptor functions. In the absence of masking by concomitant anti-analgesic excitatory opioid receptor functions, the very low residual concentrations of morphine in the CNS at >2 h after an acute injection can, nevertheless, elicit substantial long-lasting inhibitory opioid receptor-mediated antinociceptive effects. Pretreatment of 129/SvEv mice with low doses of GM1 ganglioside (0.1–1 mg/kg, i.p.) for about 30 min resulted in a marked decrease in morphine's antinociceptive potency tested within the first hour after administration of morphine and lasting for >6 h. The marked GM1-induced attenuation of morphine's antinociceptive effects in 129/SvEv mice may be due to conversion of some of the opioid receptors in these mice from an inhibitory Gi/Go-coupled to an excitatory Gs-coupled mode. Exogenous GM1 supplementation can, therefore, reverse the anomalous lack of morphine tolerance displayed by this mouse strain in comparison to SW and other mice. The present study may provide insights into factors that regulate the marked variability in nociceptive sensitivity and opioid tolerance/dependence liability among individual humans.