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Vol. 282, Issue 2, 939-944, 1997
Washington University School of Medicine, Department of Psychiatry,
St. Louis, Missouri
In earlier studies, it was shown that male rats were considerably more
sensitive to the antinociceptive properties of morphine than females in
several antinociceptive assays. The purpose of our studies was to
examine whether these male-female differences might be due to
differences in the blood and brain levels of morphine attained after
its s.c. injection rather than to intrinsic differences in the central
nervous system sensitivity to the drug. Our results confirmed that
males were considerably more sensitive than females to the
antinociceptive properties of morphine on the hot-plate test; the
ED50 in males was approximately half that found in females. These sex differences were not unique to morphine because males were
also more sensitive to the antinociceptive properties of the potent
mu agonist, alfentanil. With respect to the pharmacokinetics of morphine, we found that there was a linear relationship in both
males and females between the dose of morphine injected and the blood
and brain levels achieved 60 min after the injection when the
sex-linked differences in morphine-induced antinociception was
greatest; no sex differences were found in the peak levels of morphine
attained in blood or brain at any dose of morphine. Furthermore, there
were no sex-linked differences in the elimination half-life of morphine
from blood and, similarly, there were no differences in the
disappearance of morphine from brain. On the basis of these data, it
appears that the sex-related differences we have observed between males
and females in the response to morphine's antinociceptive activity
cannot be explained by differences in the pharmacokinetics of morphine.
Rather, it appears that sex differences in morphine-induced
antinociception are related to inherent differences in the sensitivity
of the brain to morphine.
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