Influence of low doses of naltrexone on morphine antinociception and morphine tolerance in male and female rats of four strains

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In a recently proposed bimodal opioid receptor model, the inhibitory actions of opioids on action potential duration in dorsal root ganglion neurons have been proposed to produce antinociception, and the excitatory actions of hyperalgesia. Recent studies indicate that selectively blocking these excitatory actions with low doses of opioid antagonists enhances opioid antinociception and attenuates the development of opioid tolerance. To determine if the excitatory actions of opioids contribute to sex as well as strain differences in opioid sensitivity, the effects of morphine alone and in combination with low doses of naltrexone were examined in male and female rats of four strains. The strains examined differed in their sensitivity to opioid antinociception and magnitude of sex differences in opioid sensitivity. All testing was conducted using a thermal tail-flick procedure with the nociceptive stimulus intensity adjusted so that baseline latencies were comparable across strains/sexes. In chronic studies, the morphine dosing regimen was adjusted in each strain/sex to produce comparable levels of tolerance. In each of the strains tested, morphine produced dose-dependent increases in antinociception, with differences in morphine potency observed across strains and sexes. In male and female Sprague–Dawley and Long–Evans rats, naltrexone enhanced morphine antinociception and attenuated the development of morphine tolerance. These effects were not observed in F344 and Lewis rats, even when tests were conducted across a range of morphine and naltrexone doses. These results suggest that the ability of low doses of naltrexone to enhance opioid antinociception does not contribute to sex or rat strain differences in opioid sensitivity.

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