μ-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.

Sex and Estrus Cycle Differences in the Modulatory Effects of Morphine on Seizure Susceptibility in Mice

“…Sex differences in opioid-dependent stress-induced analgesia have been reported by many authors (15,52,53). Zubieta et al (54) suggested that µ-opioid receptor-mediated antinociceptive responses differ in men and women. Kavaliers and Innes (55) showed a sex difference in the antinociceptive properties of the endogenously released opioid peptide enkephalin.…”

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

“…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).…”

Perinatal ethanol exposure alters met-enkephalin levels of male and female rats

“…In general, it appears that social behavior increases the levels of met-enkephalin in different brain areas, although it should be noted that the findings are almost exclusively in males. Given that a sex-dependent difference has been found in delta opioid receptor immunoreactivity in the amygdala of rats [43] and that human females have increased mu receptor binding in the prefrontal cortex, amygdala, thalamus, and anterior cingulate cortex compared to males [45], sexually dimorphic involvement of opioids in social behaviors might be expected.…”