[Paleopsych] Economist: Pain perception: Sex and drugs

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Pain perception: Sex and drugs
    Jul 21st 2005

    Men and women seem to perceive pain in different ways. That may mean
    they sometimes need different pain-relief drugs

    MALES and females respond to pain differently, even as children. In
    most places, boys are expected to show a stiff upper lip when they get
    hurt, while in girls wailing is, well, girlie. In part, this
    difference is learnt--or, at least, reinforced by learning. But
    partly, it is innate. It is hard, for instance, to blame upbringing
    for the finding that boy and girl babies show different responses to
    pain six hours after birth, or that male rats are more long-suffering
    than females. It is also life-long. Ed Keogh of the University of
    Bath, in England, and his colleagues have found that women report
    feeling pain in more bodily areas than men, and also feel it more
    often over the course of their lives.

    Many researchers are therefore concluding that genetics underpins at
    least some of the difference, and that females really do feel pain
    more than males. Indeed, some go further. They think that the way men
    and women experience pain is not only quantitatively different, but
    qualitatively different, too. In other words, men's and women's brains
    process pain using different circuits. Some pain scientists therefore
    think it is only a matter of time before painkillers are formulated
    differently for men and women in order to account for this difference.

    Jeffrey Mogil, director of the pain genetics laboratory at McGill
    University in Montreal, is one of the leading advocates of such "pink
    and blue" painkillers. Pick a disease at random, he says, and the
    chances are that females and males will handle the pain associated
    with it differently. That seems to be true in mice, at least. When new
    mouse "models" of human disease are created by genetic engineers, Dr
    Mogil and his colleagues are often asked to test the engineered mice
    for their responses to pain. They consistently find differences in the
    way the mutant, diseased mice and their non-mutation-carrying brethren
    respond to painful stimuli. But, generally, those differences are seen
    more strongly in one sex than the other.

    A prescribing headache

    The latest example of such a difference is in migraine, a condition
    that is three times more common in women than in men. In 2004, a group
    of researchers led by Michel Ferrari of Leiden University in the
    Netherlands reported that they had created what they believed to be
    the first mouse model of migraine. Since some researchers argue that
    migraine is associated with heightened sensitivity to pain, they sent
    their creation to Dr Mogil for testing. He stresses that his data are
    preliminary. However, he does find a lowered pain threshold in the
    mouse migraine model compared with healthy mice--but only in females.

    Dr Mogil is now convinced that the pain response in men and women is
    mediated by different brain circuits--and not only because of his own
    observations. Obstetricians and gynaecologists have long known that
    certain drugs are particularly effective in women. Mothers in
    childbirth prefer nalbuphine to morphine, for instance. Men, however,
    report the opposite preference when they are in pain.

    Both nalbuphine and morphine work by stimulating the brain's
    endogenous-opioid receptors (endogenous opioids are the molecules that
    opium-derived drugs mimic). But opioid receptors come in several
    varieties, two of the most important of which are known as mu and
    kappa. Morphine binds to the mu receptors, while nalbuphine stimulates
    the less well-studied kappa receptors. Kappa-receptor agonists, as
    molecules such as nalbuphine are known, appear to have little or no
    pain-relieving effect in men.

    Two years ago, Dr Mogil identified the first gene known to be involved
    in modulating pain thresholds in women. Variations in this gene have
    no effect on men's responses to a kappa-receptor agonist called
    pentazocine, but they do affect the response in women. The protein
    produced by this gene, melanocortin-1 receptor, also affects hair and
    skin colour. Working in collaboration with Roger Fillingim of the
    University of Florida, Gainesville, Dr Mogil found that redheaded
    women with fair skin--who have a particular version of the
    receptor--have a heightened response to pentazocine.

    Jon Levine and Robert Gear, of the National Institutes of Health Pain
    Centre at the University of California, San Francisco, also think that
    there are fundamental differences between the sexes when it comes to
    pain. They have explored the effects of nalbuphine on post-operative
    pain in men and women who have had their wisdom teeth removed. The
    results suggest that kappa-opioid agonists not only fail to alleviate
    pain in men, they can actually make it worse.

    Dr Gear and Dr Levine believe that as well as an analgesia (ie,
    pain-suppression) circuit, the brain contains what they call an
    anti-analgesia circuit--one which, when activated, pumps pain up. They
    have shown that which circuit is activated depends not only on the
    type of receptor a drug acts on, but also the dose given. Among their
    dental patients, low doses of nalbuphine had a short-lasting analgesic
    effect in the women, but profoundly enhanced pain in the men. However,
    when they added a low dose of naloxone--a drug that blocks all types
    of opioid receptor--to the nalbuphine, the sex difference disappeared
    and pain relief was significantly enhanced in everyone. After refining
    the relative proportions of the two drugs in the mixture, they have
    succeeded in finding (and patenting) a combination that is effective
    in both sexes.

    Nor is it only the mechanism of pain perception that differs between
    the sexes. Dr Keogh and his colleagues argue that there are
    significant differences in the ways men and women cope with pain, as

    This conclusion is based on studies involving hospital patients, as
    well as others on volunteers who were exposed to a painful stimulus,
    such as an ice-water arm-bath. Using this, the researchers were able
    to measure the point at which people first notice pain, as well as
    their tolerance--the point at which they can no longer stand it. Men
    were able to minimise their experience of pain by concentrating on the
    sensory aspects--their actual physical sensations. But this strategy
    did not help women, who focused more on the emotional aspects. Since
    the emotions associated with pain, such as fear and anxiety, tend to
    be negative, the researchers suggest that the female approach may
    actually exacerbate pain rather than alleviating it.

    Dr Keogh, a psychologist, sees this difference as an effect of social
    conditioning--and uses it to point up the dangers of under-estimating
    social influences in favour of those of the genes. But it is not
    obvious why such male and female "coping strategies" should not be
    underpinned by genetics, in the same way that perceptions are.

    The evolutionary reason why men resist pain better than women is,
    however, a mystery. After all, pain is there to stop you doing bad
    things to yourself. Perhaps it is because males and females are
    exposed to different sorts of pain. Males, for instance, get into
    fights much more often than females do, and thus get wounded more
    often. On the other hand, they do not have to undergo the visceral
    pain of childbirth. And perhaps a willingness to tolerate less pain
    than men do helps to explain why women live longer than their menfolk.

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