Pain experiences are shaped by a combination of cultural, psychological, and biological factors. Because the incidence of pain disorders is higher in women, with longer duration and severity [43
], sex differences in pain have been a focus of extensive research. These studies find that women are more often diagnosed with chronic pain disorders such as migraine, complex regional pain syndrome, fibromyalgia, irritable bowel syndrome, temporomandibular disorder, and whiplash-associated disorder [34
]. The pathophysiologic process of central sensitization is thought to be common to all of these disorders. Thus, gaining a greater understanding of the central mechanisms underlying this sex difference is a crucial next step for pain research [55
The most studied endogenous pain modulatory system is the periaqueductal gray (PAG) and its descending projections to the rostral ventromedial medulla (RVM) [61
]. Pain is modulated by the PAG through the RVM that directly communicates with nociceptive neurons in the dorsal horn of the spinal cord. The PAG receives direct projections from the hypothalamus and the limbic forebrain including the frontal neocortex, amygdala, and anterior cingulate cortex [2
]—regions involved in emotional and cognitive processing of pain. Given the crucial role of this descending pain control system, some investigators have hypothesized that its dysfunction, particularly dysfunction of the PAG, may be crucial to the development and maintenance of chronic pain states [3
Animal studies indicate differences in pain inhibition between male and female animals. The spinal endorphin/µ-opioid receptor analgesic system is sexually dimorphic in rats [56
]. Even though female rats have greater numbers of PAG to RVM output neurons [80
], both morphine and pain induce more activation of PAG neurons projecting to the RVM in male rats [16
], and microinjection of morphine into the PAG produces less pain reduction in female rats [79
]. These results suggest that distal projections of the PAG may be in part explaining sex differences in pain [80
] and led us to speculate that there are similar sex-specific pain-evoked patterns of PAG connectivity in humans.
Previous functional magnetic resonance imaging (fMRI) studies on sex differences in pain reactivity indicate that men have greater pain activation of the somatosensory and insular cortex, and that women have higher medial prefrontal activation [35
]. In addition to task-related fMRI, resting-state functional connectivity studies also indicate sex differences [15
]. For instance, using the PAG as a seed, we have found that men display higher connectivity to the uncus, the insula, and the prefrontal cortex, whereas women displayed higher PAG connectivity to the middle cingulate cortex [70
As the key region in the endogenous pain modulation system, it is likely that the functional association between the PAG and other brain regions is changed when experiencing different levels of pain. We analyzed data from 3 previous experiments from our laboratory to investigate how midbrain connectivity changes when switching from low to high pain stimulation, and whether such changes in connectivity differ between men and women.