Nociception: More Pain No Gain For Women?

20. June 2017
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When women and men feel pain, their respective signalling and threshold levels often differ greatly. It is therefore all the more important to take both genders into account in research, both in studies of humans and in those conducted on laboratory animals.

For Heaven’s sake! Twice as many cages, twice as many laboratory animals! And then there’s still the unpredictable hormonal fluctuations in the body cycle of female mice! It’s not only pain researchers who would prefer to ignore the current recommendations. For studies conducted on humans as well as on animals both genders should be equally taken into account – this is the specification given by the National Institute of Health (NIH) in the USA.

Statistics from pain research clearly show how unequally the genders are taken into account: 71 articles describing mouse or rat experiments were published in the Journal of Pain. From among these, 65 were related solely to experiments using male animals, six of them using female animals and only three dealt with experiments involving both male and female rodents. Six publications contained no description of gender. The above bias is for the most part unjustified, explains Jeffrey Mogil from McGill University in Montreal, Canada, in a Nature article.

More outlay on account of mouse gender equality?

When it comes to pain research, the variability in test results is not greater with female mice than it is with males. This is by the way also the case with all other types of laboratory animals. On the contrary – if there are several males in a given cage, the effects of the struggle for rank are often reflected in the physiological data.

Are double the number of animals therefore needed in order to meet the requirements of the NIH? Mogil answers the question: “In principle, no!” This is because when looking at results large differences between male and female animals are already noticeable with small numbers of test animals. More minor differences, on the other hand, are probably not noticeable due to variation of results in general. Significant gender differences in reactions in fact would offer material for a new and future article.

The mind and hormones

The majority of patients seen specifically in pain medicine are women. This is another reason to steer research more toward the female side. Chronic pain in particular is much more common in women. Statistics show: women are more sensitive to pain and feel pain significantly more intensely than do men. The search for the exact causes of this difference between the “strong warrior” and the “frail woman” is, however, on account of many disparate findings, very laborious. The question most notably often arises in this field of study: What is cause, what is effect?

Post mortem investigations of the skin of women have shown twice the density of nerve fibres as in men. In women, the brain regions for affective pain control seem to be more active than in men. Neuropsychological studies show the processes of the brain to be very similar in both sexes when the factor “anxiousness” is excluded The mind therefore seems to play a major role in the pain sensations – as do sex hormones.

In experiments involving male rats, oestrogens showed a pronociceptive effect, that is an increase in pain sensation. In female rats where a pregnancy was simulated, high plasma concentrations of oestrogens and progesterone in contrast raised the pain threshold. In a mouse model in which a ligature of the sciatic nerve was employed to simulate neuropathic pain, male animals recovered rapidly from this shock, whereas female animals only recovered to their normal state slowly when estradiol was supplemented.

Pain: not purely a matter of nerves

It is also becoming ever more apparent that neurons and their encasing cells are by no means the only cells involved in the origination of pain. The immune system and the nervous system are more and more merging in this research area. Microglia and cells of the immune system are significantly involved in pain, as well as in neurological diseases. Many of these have very different rates of occurrence for men and women.

Thus animal experiments have now shown that the microglia inhibitor minocycline suppresses pain in male animals in particular, but hardly does so in females. T-cells, in being part of the adaptive immune system, are especially responsible for induced hypersensitivity, and in female mice the number of these is twice as high as in males. In work conducted on T-cell deficient mice, scientists from Mogil’s laboratory were able to demonstrate that testosterone administration can terminate previously induced allodynia in female mice.

But how does testosterone have its effect? Apparently, this hormone affects the PPAR (peroxisome proliferator activated receptor) transcription factors and in this way puts the brakes on the ejection of proinflammatory mediators. Agonists of the PPARα subtype alleviated allodynia in the males, but not in the females. With PPARγ agonists exactly the reverse is true. Testosterone shifts the PPAR balance towards PPARα in T cells. P2RX4 (purine receptor 4) is found in microglia cells in cases of neuropathic pain, but only in animals with high testosterone levels – that is, males. The same is seen when looking at the receptor of the congenital immune system, TLR4. Lipopolysaccharide injections lead to a rise in mouse TLR4 levels in both sexes, but the corresponding TLR4-dependent pain reaction is again dependent on the testosterone level.

Painless encounter among men

In women, menopause is an important and decisive point with regards to pain sensitivity as well. The lower level of oestrogen generally leads to the reduction of pain, especially those associated with headaches. In return, however, new painful diseases often appear, such as osteoporosis or arthralgia, which are no minor causes of suffering.

Returning to the topic of test animals: pain sensitivity is affected not only by the animal’s gender, but also for instance by that of the main researcher or the animal technician. Male animals react to male researchers with stress-induced analgesia – something which is significantly less pronounced in females. This effect can be reproduced by using worn clothing, as well as nesting material, obtained from unrelated mammalian males.

Should women now go looking for a female doctor? Might testosterone administration relieve pain in women? What kind of pain relievers tend to help men, which more likely women? The interweaving of influences on pain sensation seems to be much too complicated at the moment for simple answers to be able to be given. It’s probably the case that many of the findings obtained with mice and rats also apply to human pain. Preclinical studies which focus only on one gender of laboratory animals therefore probably equate to being research from a bygone time.

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