Pronociceptive and Antinociceptive Effects of Estradiol through Endogenous Opioid Neurotransmission in Women

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Abstract
Prominent interindividual and sex-dependent differences have been described in responses to sustained pain and other stressful stimuli. Variations in μ-opioid receptor-mediated endogenous opioid neurotransmission may underlie some of these processes. We examined both baseline μ-opioid receptor levels and the activation of this neurotransmitter system during sustained pain using positron emission tomography in a sample of young healthy men and women. Women were studied twice, during low and high estrogen states. The high-estrogen state was associated with regional increases in baseline μ-opioid receptor availabilityin vivoand a greater activation of endogenous opioid neurotransmission during the pain stressor. The latter did not differ from that obtained in males. During the low estrogen condition, however, significant reductions in endogenous opioid tone were observed at the level of thalamus, nucleus accumbens, and amygdala, which were associated with hyperalgesic responses. Estrogen-associated variations in the activity of μ-opioid neurotransmission correlated with individual ratings of the sensory and affective perceptions of the pain and the subsequent recall of that experience. These data demonstrate a significant role of estrogen in modulating endogenous opioid neurotransmission and associated psychophysical responses to a pain stressor in humans.