SexX matters when it comes to pain

The neurobiology of sex differences in pain remain poorly understood. Yu et al., 2021Yu W. Pati D. Pina M.M. Schmidt K.T. Boyt K.M. Hunker A.C. Zweifel L.S. McElligott Z.A. Kash T.L. Periaqueductal gray/dorsal raphe dopamine neurons contribute to sex differences in pain-related behaviors.Neuron. 2021; (this issue): 1365-1380Google Scholar provide new insight by demonstrating that activation of dopaminergic projections from PAG to BNST provides substantial pain relief in male mice but virtually none in females. The neurobiology of sex differences in pain remain poorly understood. Yu et al., 2021Yu W. Pati D. Pina M.M. Schmidt K.T. Boyt K.M. Hunker A.C. Zweifel L.S. McElligott Z.A. Kash T.L. Periaqueductal gray/dorsal raphe dopamine neurons contribute to sex differences in pain-related behaviors.Neuron. 2021; (this issue): 1365-1380Google Scholar provide new insight by demonstrating that activation of dopaminergic projections from PAG to BNST provides substantial pain relief in male mice but virtually none in females. Pain is a universal experience. Everyone experiences it, no matter your income, skin color, political affiliation, marital status, BMI, or the goodness of your heart. But how much pain a person feels, and how they respond to it, varies greatly. Understanding why this is the case is fundamental to effective mitigation of pain, and yet we have failed utterly at incorporating this thinking into either the clinical management or basic science of pain. A report by Yu et al., 2021Yu W. Pati D. Pina M.M. Schmidt K.T. Boyt K.M. Hunker A.C. Zweifel L.S. McElligott Z.A. Kash T.L. Periaqueductal gray/dorsal raphe dopamine neurons contribute to sex differences in pain-related behaviors.Neuron. 2021; (this issue): 1365-1380Google Scholar in this issue starkly highlights our poor understanding of one of the simplest sources of variation in pain: sex, or in the case of humans, gender. That pain is experienced differently by men and women has long been known, but understanding why has been enormously challenging. In 2006, members of the Sex, Gender, and Pain Special Interest Group of the International Association for the Study of Pain met to discuss the status of our understanding and make recommendations for future emphasis. They concluded at the time that there was convincing evidence that, on average, women experience more pain than men. However, they further concluded there was insufficient evidence to warrant sex-specific pain interventions. In essence, the complex interplay of different origins of pain, psychosocial factors, hormonal milieu, and lived experience overwhelmed any evidence of a biological basis for sex differences in pain (Greenspan et al., 2007Greenspan J.D. Craft R.M. LeResche L. Arendt-Nielsen L. Berkley K.J. Fillingim R.B. Gold M.S. Holdcroft A. Lautenbacher S. Mayer E.A. et al.Consensus Working Group of the Sex, Gender, and Pain SIG of the IASPStudying sex and gender differences in pain and analgesia: a consensus report.Pain. 2007; 132: S26-S45Abstract Full Text Full Text PDF PubMed Scopus (667) Google Scholar). They called for more research. Sadly, that research did not come in any strong measure until the adoption of policies from the NIH in the U.S. and the CIHR in Canada that required either the inclusion or at least consideration of both sexes in preclinical research. Since the 1990s, the majority of basic neuroscience research has been conducted exclusively on male subjects, but the field of pain research has been a stand-out for its neglect of females (Mogil and Chanda, 2005Mogil J.S. Chanda M.L. The case for the inclusion of female subjects in basic science studies of pain.Pain. 2005; 117: 1-5https://doi.org/10.1016/j.pain.2005.06.020Abstract Full Text Full Text PDF PubMed Scopus (229) Google Scholar), despite clear demonstrations of divergent pathways mediating pain (Mogil, 2020Mogil J.S. Qualitative sex differences in pain processing: emerging evidence of a biased literature.Nat. Rev. Neurosci. 2020; 21: 353-365https://doi.org/10.1038/s41583-020-0310-6Crossref PubMed Scopus (97) Google Scholar), including the discoveries that pain hypersensitivity in males relies on microglia whereas the same response is achieved by T lymphocytes in females (Sorge et al., 2015Sorge R.E. Mapplebeck J.C. Rosen S. Beggs S. Taves S. Alexander J.K. Martin L.J. Austin J.S. Sotocinal S.G. Chen D. et al.Different immune cells mediate mechanical pain hypersensitivity in male and female mice.Nat. Neurosci. 2015; 18: 1081-1083https://doi.org/10.1038/nn.4053Crossref PubMed Scopus (649) Google Scholar) and that there are sex differences in the neural circuits mediating opioid-induced analgesia (Loyd and Murphy, 2014Loyd D.R. Murphy A.Z. The neuroanatomy of sexual dimorphism in opioid analgesia.Exp. Neurol. 2014; 259: 57-63https://doi.org/10.1016/j.expneurol.2014.04.004Crossref PubMed Scopus (49) Google Scholar). Even the status of microglia within the periaqueductal gray (PAG) differs markedly by sex and both predicts and directs the differential response to morphine (Doyle et al., 2017Doyle H.H. Eidson L.N. Sinkiewicz D.M. Murphy A.Z. Sex Differences in Microglia Activity within the Periaqueductal Gray of the Rat: A Potential Mechanism Driving the Dimorphic Effects of Morphine.J. Neurosci. 2017; 37: 3202-3214https://doi.org/10.1523/JNEUROSCI.2906-16.2017Crossref PubMed Scopus (89) Google Scholar). But these studies were not without impact, as neuroscience trainees were quick to note the importance and value of including both sexes in research, as was the case for Waylin Yu, a new graduate from the Kash lab and first author on this study. The PAG is a key brain region in the integration of signals relevant to pain perception and pain responding. Kash and colleagues report that selectively activating the dopamine cells of the ventrolateral PAG induces analgesia in male mice, but has zero effect on females. But pain comes in many forms. We all know from experience that the pain from a burn is different compared to that from a cut or a bruise, while the pain from a muscle spasm or arthritis is different still. Pain can be acute or chronic, and chronic pain can make acute pain more severe. Kash and colleagues found the response to a wide range of acute painful stimuli could be lessened in males but not females, including the equivalent of a pin prick and touching a hot stove, i.e., acute mechanical versus thermal pain. They then threw in inflammation for good measure, as if your foot was swollen from an infection and then you stubbed your toe. Still, only males were afforded relief from the pain by stimulating the PAG dopamine neurons. They next asked where those dopamine neurons were projecting to, and, based on prior knowledge, targeted the bed nucleus of the stria terminalis (BNST). Activating the dopamine nerve terminals coming from the PAG selectively in the BNST had the same sex-specific effect as activating the cell bodies. Both the mechanical and thermal acute pain tests rely on the latency for the mouse to withdraw its paw away from the offending stimulus, in essence a reflex. But other forms of pain induce distinct adaptive responses. Only women experience the pain of uterine contractions, and they are more likely to suffer from irritable bowel syndrome, both considered visceral pain. Kash and colleagues also investigated this form of pain, which is measured by multiple responses. This includes neglecting to engage in nesting, a favorite activity of mice, and acutely writhing or moving around following induction of the pain. Here they found that stimulating the PAG-BNST dopamine pathway had no effect on nesting, with both sexes completely losing interest in keeping a tidy house while in pain. However, females exhibited more writhing and overall locomotion if the dopamine pathway was stimulated, while males were impervious. Mice can't tell us if they are in pain, but the behavioral response of the females suggests they were experiencing more pain when the PAG-BNST pathway was stimulated. While the PAG is a central way station for integrating information relevant to pain, the BNST serves the same role for information relevant to sociability. Stimulating the dopamine projection to BNST had no impact on the desire of mice to spend time with each other versus an inanimate object, but did modestly increase locomotion, more so in females, and in a context dependent manner. At this point the authors were faced with a bit of a mystery. Why does a pathway that seems to be anatomically similar in males and females provide relief from pain in one sex and promote locomotion in the other? Tangential to the study of pain is that of addiction, particularly addiction to narcotics, which often has origins in pain management. Indeed, one need look no further than the recent opioid abuse epidemic that has swept the United States to know the cost of pain to society. Back pain is one of the most common sources of disability, with up to 30% of adults in the U.S. reported to experience back pain lasting two or more days. Evidence now suggests that prescription opiates to treat that pain have been the dominant source of the epidemic. Females progress to drug dependence more quickly than males, and this is believed to be at least in part due to increased dopamine release at the nucleus accumbens (Becker et al., 2012Becker J.B. Perry A.N. Westenbroek C. Sex differences in the neural mechanisms mediating addiction: a new synthesis and hypothesis.Biol. Sex Differ. 2012; 3: 14https://doi.org/10.1186/2042-6410-3-14Crossref PubMed Scopus (204) Google Scholar). Kash and colleagues interrogated the neurophysiology of PAG dopamine release and response in the BNST and found more similarities than differences, with the exception that D1 receptor-gated depolarization was greater in males. They also confirmed that the anti-nociceptive effect of stimulating the PAG-BNST pathway definitively requires dopamine. Like any good study, this one creates as many questions as it answers. A clear connection is made between dopamine activation and pain relief in males, but it remains a mystery as to why the same is not true for females. Pain is among the most fundamentally important of all properties, common to all animals and essential to survival. Why would something so basic and subject to all the power that evolution can bring to bear be so different for males and females? Is there an advantage to one mechanism for pain management in males that is not realized in females? Or are there intrinsic constraints around reproductive physiology, the most profoundly sexually dimorphic aspects of the nervous system, that require a "workaround" in one sex versus the other? The BNST is among the most sexually dimorphic brain regions and is essential for both the sex-specific control of gonadotropin release from the pituitary (Polston et al., 2004Polston E.K. Gu G. Simerly R.B. Neurons in the principal nucleus of the bed nuclei of the stria terminalis provide a sexually dimorphic GABAergic input to the anteroventral periventricular nucleus of the hypothalamus.Neuroscience. 2004; 123: 793-803Crossref PubMed Scopus (60) Google Scholar) and male mating behavior (Lenschow and Lima, 2020Lenschow C. Lima S.Q. In the mood for sex: neural circuits for reproduction.Curr. Opin. Neurobiol. 2020; 60: 155-168https://doi.org/10.1016/j.conb.2019.12.001Crossref PubMed Scopus (8) Google Scholar). Likewise, the PAG is also intimately involved in the regulation of reproductive behavior of both males and females (Lenschow and Lima, 2020Lenschow C. Lima S.Q. In the mood for sex: neural circuits for reproduction.Curr. Opin. Neurobiol. 2020; 60: 155-168https://doi.org/10.1016/j.conb.2019.12.001Crossref PubMed Scopus (8) Google Scholar). Do these features of the BNST preclude it from responding to the PAG dopamine input similarly in males versus females? Or did females evolve an entirely different mechanism for pain management that somehow suits them better? These are the big picture questions we would be wise to ask if we are going to advance the therapeutic treatment of pain for all of those who suffer it. Periaqueductal gray/dorsal raphe dopamine neurons contribute to sex differences in pain-related behaviorsYu et al.NeuronMarch 18, 2021In BriefYu et al. demonstrate that dopamine neurons in the periaqueductal gray/dorsal raphe target the bed nucleus of the stria terminalis to reduce pain sensitivity in male mice and increase locomotion in female mice. Dopamine signaling is required for sex-specific expression of these adaptive behaviors. Full-Text PDF Open Archive