It has been known for many years that men and women have different pain thresholds—measurable, quantitative differences in both their perception of and reaction to pain. Now researchers are discovering there are also qualitative genetic and neurochemical differences between the pain processing systems of men and women. These qualitative differences, says Jeffrey Mogil (McGill University, Montreal, Canada), are “much more important than the fairly small differences in pain thresholds between the sexes” and could lead to the development of different pain drugs for men and women—“blue and pink pills if you like”.

Many things influence an individual's sensitivity to pain, says clinical psychologist Roger Fillingim (University of Florida College of Dentistry, Gainsville, FL, USA): sociocultural factors, age, the type of painful stimulus, genetic makeup—all these factors and more combine to produce a very personal experience of pain. And if clinicians are ever going to optimise pain treatment based on a person's characteristics, Fillingim says, they are clearly going to have to take into account both the patient's sex (the individual's biological classification of being male or female) and gender (the individual's self-representation of being male or female).

By drawing on the available research evidence, several generalisations can be made about men and women with respect to pain, says anaesthetist Anita Holdcroft (Chelsea and Westminster Hospital, London, UK). Men have a higher threshold and tolerance to experimentally induced pain than women, for example. Similarly, in the community, women report more pain than men and more often develop chronic pain disorders. And, although men report pain in specific areas, women tend to report more diffuse pain, which can lead to misdiagnosis.

There is also some evidence that men and women react differently to some pain drugs.

Mogil is one of these researchers. In 1993, he was working on stress-induced analgesia—the activation of pain inhibition systems in the brain by exposure to stress. In particular, he was examining the effects of an inhibitor of this endogenous analgesia system in mice.

Mogil's pre-dinner analysis revealed that the test drug only blocked stress-induced analgesia in male mice even though both sexes showed similar stress-induced analgesia in the absence of drug. This, he says, indicated that male and female animals must have at least partly separate circuits mediating stress-induced analgesia. The male system involved the N-methyl-D-aspartate (NMDA) receptor, he explains. Female mice had a separate system but used the male system when oestrogen was removed.

later research by Robert Gear and Jon Levine (University of California School of Dentistry, San Francisco, CA, USA) showed that κ opioids were better analgesics in women than in men.

Subsequent research showed that Mogil's female stress-induced analgesia system and sensitivity to κ opioids mapped to the same region of the mouse genome and Mogil has now identified a candidate gene involved in female pain modulation. Surprisingly, this gene is the melanocortin 1 receptor, variations in which also affect hair and skin colour. In collaboration with Fillingim, Mogil has shown that while variations in this receptor have no effect on the analgesic response to the κ opioid pentazocine in men, red-headed, fair-skinned women who carry a specific melanocortin 1 receptor mutation have a heightened response to the drug (Proc Natl Acad Sci USA; 2003; 100: 4867–72).

Gear, who cautions that the κ-opioid system is very different in animals and people, does not believe that this is the whole explanation for sex differences in κ-opioid responses. It may not just be that something about female biology enhances κ-opioid analgesia, says Gear –something in males could antagonise the analgesia. “We think that κ-opioids produce analgesia and antianalgesia, perhaps by acting at different receptor subtypes”, continues Gear. “Our prediction is that men have more antianalgesia receptors than women”, a hypothesis that Gear is currently testing.

μ opioids, by contrast, are widely used but again there is a sex difference in their analgesic effectiveness. Jon-Kar Zubieta (University of Michigan, Ann Arbor, MI, USA) first compared μ-opioid receptors in men and women in 1999. Using positron emission tomography, he found that women have more μ,-opioid receptors in many brain regions than men and that these sex differences are most prominent in women of reproductive age. Differences like these, says Zubieta, are clinically important because although μ opioids reduce pain better in women than men, women may also experience more side effects.

μ,-opioid receptors are part of the endogenous stress-induced analgesia system and when Zubieta investigated whether the regulation of this endogenous antinociception system was the same in men and women, he found that women did not activate their endogenous pain-control systems as well as men. These initial experiments were done at a time during the menstrual cycle when oestrogen concentrations are low, but in February Zubieta presented preliminary data at the American Association for the Advancement of Science meeting showing that oestrogen can activate the endogenous μ,-opioid system. Maybe, he speculates, women generally have a low pain threshold to ensure that they take better care of themselves and are thus able to propagate the species. In pregnancy, however, pain would need to be suppressed, he suggests, hence the oestrogen-dependent activation of the endogenous μ,-opioid system.

Zubieta's speculation is a variant on a popular but controversial theory that tries to explain why men have a higher threshold for traumatic pain than women. During evolution, the theory suggests, as hunters, men would have needed to deal with this type of pain effectively whereas women would have needed a pain system that could deal with the visceral pain of childbirth. One big problem with this theory, says Mogil, is that it is untestable. His preferred, albeit equally untestable, explanation is based on the existence of a large overlap between the systems for analgesia and reproduction in brain anatomy and neurochemistry. Maybe, he suggests, the reproductive system developed first with all its sex differences and the analgesic system came along later and “borrowed the same circuitry”.

Yet another piece of this sexually dimorphic circuitry recently yielded its secrets to Adron Harris (University of Texas at Austin, USA) and Allan Basbaum (University of California, San Francisco, USA). “Many kinds of drugs relieve pain”, explains Harris, “and because each has a different molecular site of action in the brain, it has always been assumed that pain relief is a complex cascade”. Harris and Basbaum discovered that they could reduce the pain-relieving effects of many analgesic drugs and eliminate the sex differences in pain threshold in mice by removing a single protein, GIRK2 (a G-protein coupled inwardly rectifying potassium channel; Proc Natl Acad Sci USA 2003; 100: 271–76, 277–82). When Harris analysed his data by the sex of the knockout mice, he found to his surprise that although the effect of GIRK2 removal on analgesic efficacy varied with drug type, it was generally greater in male than in female mice. This suggests that GIRKs are not as functional in females as in males, says Basbaum. And, adds Harris, “that females have a more complicated approach to pain relief than males”, a result similar to that reported by Mogil.

Males are better at tolerating pain than females because of a key difference in how the sexes transmit pain messages, researchers have found.

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