The Discerning Rodent
(appeared on 30th April 2014)

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The expression, “I smell a rat,” to convey that all is not well, has been turned around by laboratory mice, says S.Ananthanarayanan.

Rodents have been found to respond like they are stressed, and they put on their guard, when they are exposed to the smell of male experimenters. It was the same with any male, even of other species, but not when the experimenters were women. “I smell a man,” they seemed to say, while they tensed up and showed all indicators of stress, when exposed to male smells.

A group of researchers from Montreal, Alabama, Pennsylvania, and Stockholm report in the journal, Nature Methods, that “male-related stimuli induced a robust physiological stress response that results in stress-induced” suppression of pain. The feature of suppression of pain was hence used to conclude that there was stress. And then, the group found a method of estimating the pain experienced by a rodent.

Stress and fear

There is basis to believe that stressful situations reduce the sensation of pain, a reaction known as stress induced analgesia (SIA). Reduction of pain can come about in different ways- like massaging the place where one has been struck, or taking an aspirin for a headache, or for severe pain, there are strong agents, like morphine, The body also manufactures its own chemical to deaden pain, like during exercise or when a person is faced with an emergency. While the action of morphine and opium derived chemicals are known to act at specific receptors in brain cells, the agents generated by the body, either as response to exercise or in fight or fly situations, also affect the same receptors. That exercise has the effect of reducing the response to pain has been amply proved in trials. A possible mechanism is that it is increased blood pressure during exercise is the reason, but there is evidence that there are other reasons as well.

The reduction in sensation of pain in the face of fear is also well documented. Why this response should have got wired in, in the course of evolution, is evident, as suppression of pain during an emergency has clear survival value. Here again, the mechanism is not quite understood. The release of opiates, however, is well established, although there may be other factors But the position is accepted that stressful situations, psychological, as in fear, or physical, like in exercise, bring about a reduction in the sensation of pain.

Estimating pain

While there are reflexes, like withdrawing a limb when it is struck or exposed to heat, there are many problems in coming to know how severely an animal, or even a person challenged in cognition or speech, feels pain. A few years ago, a group at Montreal, Vancouver and Lieden developed a method of using facial expression by mice, the Rodent Grimace Scale, to measure pain. It is known that new born babies and persons born blind, both show similar facial emotions on their faces and the ability to communicate pain would also have benefits for animals that live in groups.

In order to try calibrate the nature of facial expression against intensity of pain, the group carried out extensive surveys, using video cameras, of facial expressions of mice which had been injected with a chemical that caused stomach constrictions, and hence pain. The group then compiled panels of photographs which showed a sequence of ‘pain’ expression, which the experimenters soon learnt to interpret quite efficiently. “The ability to reliably and accurately detect pain, in real time, using facial expression might offer a unique and powerful scientific tool in addition to having obvious benefits for veterinary medicine,” they said.

Estimating stress

The current group of researchers used this instrument, of the Rodent Grimace Scale, to estimate the level of pain experienced by mice under different conditions, to see if the conditions affected their sensitivity to pain. The motivation was to verify the observation that reaction to pain in mice appears to be blunted when experimenters are present.

Pain was induced by injection of chemicals in the ankles and the mice were observed through plexiglass windows, with and without the presence of an experimenter at a distance of half a meter. The results were an unmistakable 36% reduction in pain sensation in the presence of a male observer, but no reduction if the observer was a woman! The same result was also seen with rats in place of mice and it was seen that the pain reduction was greater in female mice than in males.

The effect was shown to be based on smell, as the same results were obtained when the male or female observers were replaced by T shirts the experimenters had worn overnight. The reduction of pain was also confirmed using a test where licking behavior, in addition to grimacing, takes place. In this test, it was seen that with higher doses of the chemical, reduction in pain took more than the smell of the male observer, there was also need for the male to be seen. The tests were repeated, using the chemicals found in secretions of human bodies, both that were the same as well as those that were different in males and females, and it was found that it is the sex signaling molecules that seemed to be relevant.

As the chemo-signaling molecules are found to be the structurally the same in all mammals, the tests were repeated with bedding material from cages of other animals and it was found that it was the smell from males that produced analgesia. In fact, it was found that smells from castrated males did not have the effect, which strongly suggests that it is the male sex hormones that are relevant.

Further studies were carried out biochemical changes in the mice bodies when exposed to male smells. Here, it was found that the levels of corticosterone, a steroid hormone that signals stress, was increased, in the same way as when the animals had been physically restrained for a 15 minute period, or had been forced to carry out a3 minute swim. Even other indicators of stress, like the level of fecal deposit, or rectal temperature, showed stress upon being exposed to males or male smells.

The conclusion is that the presence of males is innately stressful, across species. Many results of research that is carried out using the behavior of mice are found not to be the same when the same experiments are carried out in another laboratory in the same way. The current findings suggest that this may be because the experimenters were not of the same sex in the two cases. Reports of experiments are elaborate in listing the conditions of work, but do not state the sex of the researchers. In some cases, the reporter is even restrained from stating the sex of the experimenter. But the fact that this detail is relevant, to the advantage of the woman, should lead to relaxing such controls, in the interest of science!

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