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

Abstract

Prominent interindividual and sex-dependent differences have been described in responses to sustained pain and other stressful stimuli. Variations in -opioid receptor-mediated endogenous opioid neurotransmission may underlie some of these processes. We examined both baseline -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 -opioid receptor availability in vivo and 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 -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.

Negative affect, pain and sex: The role of endogenous opioids

“…In contrast, pain ratings were unrelated to discouragement in placebo recipients. Subcortical opioid neurotransmission may be diminished in women in low-oestrogen states (Smith et al, 2006), but this does not account for the present findings. Instead, the findings imply that a hyperalgesic effect of psychological distress was tempered by opioid release, particularly in women.…”

“…Smith et al (2006) reported that activation of endogenous opioid neurotransmission in the brain during sustained pain was similar in men and women in a high oestrogen state, but was greater in women in high than low oestrogen states. Despite this, fluctuations across the menstrual cycle are inconsistent and relatively minor for most forms of experimentally-induced pain, including cold-induced pain (Sherman and Le Resche, 2006;Kowalczyk et al, 2006).…”

“…For example, women experience more severe post-operative pain and require more morphine than men to achieve a similar degree of analgesia (Cepeda and Carr, 2003;Aubrun et al, 2005). This may be due, in part, to a decrease in µ-opioid receptor availability and suppression of endogenous opioid responses to pain during low oestrogen states (Zubieta et al, 2002;Smith et al, 2006). On the other hand, µ-opioid receptor binding is greater in various cortical and subcortical brain regions of women than men (Zubieta et al, 1999).…”

Human Mu Opioid Receptor ( OPRM1 A118G) polymorphism is associated with brain mu-opioid receptor binding potential in smokers

“…Further, the current study was designed to eliminate carryover effects of smoking by scanning smokers on two separate occasions. It will be important in future studies to include sufficient numbers of males and females, as the behavioral effects of this polymorphism may be sex specific (14,18,35), and female sex and estradiol alter MOR binding availability (36,37).…”

“…Six sequential 10-min long scans were acquired starting immediately after slow bolus injection (over 10 min) of 3-15 mCi [ 11 C]carfentanil, so as not to exceed 0.03 μg/kg. The dose of [ 11 C]carfentanil administered was based on published PET studies (36,47,48). The range of specific activity for [ 11 C]carfentanil was 1,500-3,000 mCi/μmol.…”