mu-opioid receptor-mediated antinociceptive responses differ in men and women

Abstract

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.

Figures

Fig. 1.

Changes in the state of activation of the μ-opioid system during intensity-controlled sustained muscle pain in males and females. Brain areas are shown in which significant changes in regional in vivo μ-opioid receptor availability from saline control to sustained pain were obtained in men (left side of the image) and women (right side of the image). These are shown from anterior (toppart of the image) to posterior (bottompart of the image), with their corresponding ICBM y coordinates: in males, nucleus accumbens, amygdala, ventral pallidum/substantia innominata, and thalamus; in females, nucleus accumbens, and ventral pallidum/substantia innominata. Regions in which increased activation or reductions in the state of activation were obtained are indicated at each level. Z scores of statistical significance are represented by the pseudocolor scale on the right sideof the image and are superimposed over an anatomically standardized MRI image in coronal views. The left side corresponds to the side ipsilateral to pain, and the right side corresponds to the contralateral side.

Fig. 2.

Individual data for baseline (control) and pain-induced changes in nucleus accumbens μ-opioid in vivo receptor availability in men and women. Individual data points forBmax/Kdvalues obtained in the nucleus accumbens for the sample of men and women studied during placebo and pain conditions are shown. Note the consistent reductions in pain-induced in vivo receptor availability in males and the larger variability in the responses of females to the same stimulus intensity. Four women showed increases in μ-opioid system activation (lower in vivo μ-opioid receptor availability during pain), and the reminder showed reductions in the state of activation of the system (increase in in vivo receptor availability).

Fig. 3.

Sex differences in the activation of the μ-opioid system during intensity-controlled sustained muscle pain. Brain areas are shown in which significantly larger magnitudes of μ-opioid system activation were observed in males compared with females during their early follicular phase. These are shown from anterior (toppart of the image) to posterior (bottompart of the image), with their corresponding ICBM y coordinates: nucleus accumbens, amygdala, ventral pallidum/substantia innominata, and thalamus. Z scores of statistical significance are represented by the pseudocolor scale on the left side of the figure and are superimposed over an anatomically standardized MRI image in coronal views.

Fig. 4.

Correlations between the magnitude of regional activation of the μ-opioid system and MPQ affective and sensory subscale scores in males and females. Graphs show the individual data points and correlations between the changes inin vivo μ-opioid receptor availability from placebo to pain conditions in males (filled circles andsolid lines) and females (open circlesand dotted lines), as well as MPQ affective and sensory subscale scores. Negative values of change (in parentheses) reflect the activation of the μ-opioid system and reductions in μ-opioid receptor availability in vivo. Correlations with MPQ affective scores (contralateral anterior thalamus) and with MPQ sensory scores (ipsilateral amygdala and accumbens) are shown. The dashedline depicts 0.00 change and is presented as a visual aid in data interpretation.