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