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Published on: March 11, 2017
by JR Thorpe for Bustle:
It’s been known for quite a long time that women experience pain in different volumes, and perhaps in different ways, to men. The gendered nature of pain is an intriguing thing; it seems that women and men have biological responses that encode how much pain we experience, what kinds of things might dim that pain, and our proneness to pain-related illnesses. And now we’re on the threshold of new therapies that may address a particular aspect of why women experience more chronic pain, located in an odd place: the immune system.
We tend to think of pain as just contained in the nerves, spinal cord, and brain, but it’s actually a hugely complicated business, and its interactions with a particular part of the body’s immune arsenal are the target of new studies. The particular focus of the research that’s just come out, from scientists at Georgia State, was on the fact that female bodies respond so remarkably differently to opioids, and whether or not this had something to do with immune response (spoiler: it did); but as we’ll discover, that particular discovery is just part of a swathe of emerging understandings on how pain is gendered and why.
Pain imbalance may one day be a thing of the past, but to understand how that might happen, let’s get into a discussion about pain, morphine, the female body, and a really aggravating part of the immune system.
The researchers took on a known issue in pain medication: the fact that women often don’t respond with the same success to opioid pain medication as men. The reason for this pain discrepancy, the scientists theorized, might be in the brain’s microglia, a central part of its immune system.
Microglia seem to be an integral part of a healthy brain’s functioning. They’re the central nervous system’s primary line of defense against problems, and when they detect an issue, they “activate” to destroy potential threats, remove damaged cells, and manage the brain’s inflammatory response to trouble. They can also, however, be seriously destructive. “It is widely accepted,” one research paper from 2013 notes, “that microglial-mediated inflammation contributes to the progression of Alzheimer’s disease.” While the microglial system is the brain’s army, it can also turn on itself and create havoc, which is why the scientific method behind this study is so important: you can actually turn microglia off.
By fiddling with the brain’s signaling system, they can simply be made inactive, and it doesn’t seem to have terrible after-effects for neural health or success. Previously this has been a focus for helping people with the beginnings of neurodegenerative disease (soon, dementia sufferers may go to get their microglia knocked out as part of normal treatment, which would be a weird day at the hospital), but this new research indicates it’s got something else to do: give a gendered response to pain.
The scientists wanted to test whether the fact that women often require two-to-three times the amount of morphine as men to achieve the same result might be something to do with microglia activating in women’s brains. What they found was incredibly interesting: when they knocked out the actions of microglia in female mice, they discovered that their responsiveness to opioid pain relief suddenly reached the same level as males’. At one stroke, they reduced the doubling or tripling of morphine to the same amount.
Male brains have microglia too, so what the hell is going on here? The scientists discovered something else, too, which may prove to be the explanation we’re looking for. “While no overall sex differences in the density of microglia were reported,” they said, “microglia exhibited a more “activated” phenotype in females.” And the more activated the microglia were, the poorer the female mice responded to morphine. This is an extremely odd thing on the face of it. Why would the female immune system get involved in pain processing? But as you explore it a bit, things start to get a little clearer.
Microglia may be at the root of some of the more problematic ways in which we experience pain. In 2010, for instance, research found that neuropathic pain, a kind of chronic pain that doesn’t come from inflammation but from problems in the nervous system, can likely be tracked down to microglia going vaguely haywire in the spinal cord. And an entire issue of Experimental Neurology back in 2012 was devoted to how microglia might interact with chronic pain in general, including evidence that it contributes to diabetic pain, pain after injury to the central nervous system, and a range of others. We’re gradually coming to understand, as one scientist put it, that “the immune cells, glia and neurons form an integrated network in which activation of an immune response modulates the excitability of pain pathways:” in other words, that microglia getting over-zealous play a key role in the continuation and formation of chronic pain of both neuropathic and inflammatory kinds.
And this is particularly important because there’s a group that’s more likely to experience chronic pain than any other: women. The likelihood of chronic pain is higher among women than men; studies have repeatedly borne this out. Perversely, women’s pain is often treated less seriously than men’s, thanks to cultural expectations about male stoicism and female emotionality, so female chronic pain sufferers may face the double whammy of lack of responsiveness to medication and lack of response from doctors.
The microglia add to a range of factors that we already know may shift the ways in which women respond differently to drugs. I’ve written before about the problems of not acknowledging gender when it comes to medication testing; our metabolisms, body fat ratios, hormonal cycles, and smaller size all affect how we absorb and respond to medication as a gender, and now it seems that the microglia activation in our immune systems have been playing havoc without being noticed. Until now.
The microglial revolution is relatively young; Nature only reported in 2012 that they were being discovered to be more than “passive sentinels.” But it’s moving fast. We now have regular experiments in which they’re being knocked out in mice, and a method by which the same experiment could be performed on human microglia is likely not far behind. Once that happens, microglia knock-out or alteration therapies could be part of normal treatment for chronic pain, particularly in women, and microglial reaction could help construct better pain responses for various medications. Good news indeed.
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