Background A frequent polymorphism of the brain-derived neurotrophic factor (BDNF) gene (val66met) has been suggested to modulate hippocampal neuronal plasticity and has been associated with individual variations in emotional reactivity traits and episodic memory. Methods The hippocampal formation was outlined in high-resolution anatomical magnetic resonance imaging (MRI) data in a sample of 36 healthy volunteers and compared between individuals as a function of the presence of the met-BDNF allele. Both whole-brain volume corrected and uncorrected data were tested for effects of genotype, sex, and age. Results The met-BDNF allele was associated with an 11% reduction in the volume of the hippocampal formation. Conclusions In spite of a relatively small sample size, the presence of the met-BDNF allele was found associated with a reduced volume of the hippocampal formation in healthy volunteers and may represent a vulnerability factor for the development of disease processes associated with the dysfunction of this brain region.

Reductions in pain ratings when administered a placebo with expected analgesic properties have been described and hypothesized to be mediated by the pain-suppressive endogenous opioid system. Using molecular imaging techniques, we directly examined the activity of the endogenous opioid system on μ-opioid receptors in humans in sustained pain with and without the administration of a placebo. Significant placebo-induced activation of μ-opioid receptor-mediated neurotransmission was observed in both higher-order and sub-cortical brain regions, which included the pregenual and subgenual rostral anterior cingulate, the dorsolateral prefrontal cortex, the insular cortex, and the nucleus accumbens. Regional activations were paralleled by lower ratings of pain intensity, reductions in its sensory and affective qualities, and in the negative emotional state of the volunteers. These data demonstrate that cognitive factors (e.g., expectation of pain relief) are capable of modulating physical and emotional states through the site-specific activation of μ-opioid receptor signaling in the human brain.

Objective: Synaptic β -endorphin and μ-opioid receptors are intimately involved in responses to stress. Sex differences noted in opioid-mediated stress response mechanisms may be due to the effects of gonadal steroids on vulnerability factors. We examined the psychophysical and μ-opioid neurotransmitter responses to a model of physical and psychological stress in women under two hormonal conditions. Design: This study was an intrasubject design during low estradiol and high estradiol states with each subject receiving a sustained pain-stress challenge and placebo in a randomized order, in each hormonal condition. Materials and Methods: Eight female healthy volunteers were studied with positron emission tomography (PET) and the selective μ-opioid radiotracer [C-11]carfentanil during the early follicular phase of the menstrual cycle (low estradiol, low progesterone state) and again during the same phase of the cycle after 7–10 days of treatment with transdermal estradiol patches (0.4 mg/day) (high estradiol, low progesterone state). Two experimental conditions were employed during each hormonal condition: a non-painful saline control state, and a 20 minute moderate pain state induced by the infusion of small amounts of hypertonic saline into the masseter (jaw) muscle. Pain was maintained at a constant level (40 VAS units) by the use of an adaptive computer controlled infusion system and every 15 second ratings of current pain by the volunteers. Measures of μ-opioid receptor binding potential (BP) were obtained with Logan plots with the occipital cortex as the reference region. μ-Opioid system activation was quantified as the reductions in BP from saline control to pain conditions. Results: Hormone treatment elevated estradiol plasma concentrations to levels comparable to those achieved during the periovulatory period. Estradiol treatment was associated with significant increases in baseline μ-opioid receptor BP in the anterior thalamus, nucleus accumbens, ventral pallidum and amygdala, bilaterally (z-values 4.0–6.6, p<0.05 after correction for multiple comparisons). Mu-opioid system activation in response to the pain challenge was enhanced after treatment with estradiol. Significantly higher μ-opioid system activation in the high estradiol, compared to the low estradiol studies, was detected in the anterior and posterior thalamus, nucleus accumbens and amygdala, bilaterally (z-values 4.8–6.7, p<0.05 after correction for multiple comparisons). Conclusion: These data demonstrate that estradiol has important effects on neurotransmitter systems, such as the endogenous opioid, which is involved in the regulation of stress and affective responses and reproduction.

BACKGROUND:Human affective responses appear to be regulated by limbic and paralimbic circuits. However, much less is known about the neurochemical systems engaged in this regulation. The mu-opioid neurotransmitter system is distributed in, and thought to regulate the function of, brain regions centrally implicated in affective processing.OBJECTIVE:To examine the involvement of mu-opioid neurotransmission in the regulation of affective states in healthy human volunteers.DESIGN:Measures of mu-opioid receptor availability in vivo were obtained with positron emission tomography and the mu-opioid receptor selective radiotracer [11C]carfentanil during a neutral state and during a sustained sadness state. Subtraction analyses of the binding potential maps were then performed within subjects, between conditions, on a voxel-by-voxel basis.SETTING:Imaging center at a university medical center.PARTICIPANTS:Fourteen healthy female volunteers. Intervention Sustained neutral and sadness states, randomized and counterbalanced in order, elicited by the cued recall of an autobiographical event associated with that emotion.MAIN OUTCOME MEASURES:Changes in mu-opioid receptor availability and negative and positive affect ratings between conditions. Increases or reductions in the in vivo receptor measure reflect deactivation or activation of neurotransmitter release, respectively.RESULTS:The sustained sadness condition was associated with a statistically significant deactivation in mu-opioid neurotransmission in the rostral anterior cingulate, ventral pallidum, amygdala, and inferior temporal cortex. This deactivation was reflected by increases in mu-opioid receptor availability in vivo. The deactivation of mu-opioid neurotransmission in the rostral anterior cingulate, ventral pallidum, and amygdala was correlated with the increases in negative affect ratings and the reductions in positive affect ratings during the sustained sadness state.CONCLUSIONS:These data demonstrate dynamic changes in mu-opioid neurotransmission in response to an experimentally induced negative affective state. The direction and localization of these responses confirms the role of the mu-opioid receptor system in the physiological regulation of affective experiences in humans.

Sex differences in the experience of clinical and experimental pain have been reported. However, the neurobiological sources underlying the variability in pain responses between sexes have not been adequately explored, especially in humans. The endogenous opioid neurotransmitters and mu-opioid receptors are centrally implicated in responses to stress, in the suppression of pain, and in the action of opiate analgesic drugs. Here we examined sex differences in the activation of the mu-opioid system in response to an intensity-controlled sustained deep-tissue pain challenge with positron emission tomography and a mu-opioid receptor-selective radiotracer. Twenty-eight young healthy volunteers (14 men and 14 women) were studied during saline control and pain conditions using a double-blind, randomized, and counterbalanced design. Women were scanned during the early follicular phase of their menstrual cycles after ovulatory cycles. Significant sex differences in the regional activation of the mu-opioid system in response to sustained pain were detected compared with saline controls. Men demonstrated larger magnitudes of mu-opioid system activation than women in the anterior thalamus, ventral basal ganglia, and amygdala. Conversely, women demonstrated reductions in the basal state of activation of the mu-opioid system during pain in the nucleus accumbens, an area previously associated with hyperalgesic responses to the blockade of opioid receptors in experimental animals. These data demonstrate that at matched levels of pain intensity, men and women during their follicular phase differ in the magnitude and direction of response of the mu-opioid system in distinct brain nuclei.

The endogenous opioid system is involved in stress responses, in the regulation of the experience of pain, and in the action of analgesic opiate drugs. We examined the function of the opioid system and mu -opioid receptors in the brains of healthy human subjects undergoing sustained pain. Sustained pain induced the regional release of endogenous opioids interacting with mu -opioid receptors in a number of cortical and subcortical brain regions. The activation of the mu -opioid receptor system was associated with reductions in the sensory and affective ratings of the pain experience, with distinct neuroanatomical involvements. These data demonstrate the central role of the mu -opioid receptors and their endogenous Ligands in the regulation of sensory and affective components of the pain experience.