Sunday, May 04, 2014

Not tonight dear, I had zymosan A injected into my hind paw

We now have definitive proof that the propensity of womankind to postpone sex due to a headache is of evolutionary origin! This annoying habit has been traced back directly to a strain of ovariectomized CD-1® IGS mice supplied by Charles River.

In a naturalistic design that precisely mimics the mating habits of humans, sexual receptivity was induced in the female mice with subcutaneous injections of estradiol. Then the female mice and their preferred male partners were injected in various body parts with two different compounds to induce inflammatory pain. Lo and behold, the mounting behaviors of male mice were hardly deterred by these painful treatments, but the females declined sexual congress and hid from the males.

“These findings suggest that the well known context sensitivity of the human female libido can be explained by evolutionary rather than sociocultural factors, as female mice can be similarly affected,” concluded the authors (Farmer et al., 2014).

Of Mice and Women

This study was published in the Journal of Neuroscience, and the strongly worded quote above is how the authors chose to conclude their abstract. They go to great lengths to “prove” that the loss of libido was due to lack of sexual motivation in the female mice, rather than a direct consequence of pain. The authors also stretch the clinical applicability (and evolutionary validity) of their work a bit beyond belief, in my view. Why? Perhaps because promoting a viable animal model of low sexual motivation in women will ultimately serve drug development purposes (Farmer et al., 2014):
The link between pain and sexual motivation is evident in human sexual relations. The widespread aphorism, “Not tonight, dear, I have a headache” refers to a lack of sexual motivation due to pain. No clinical data exist on the direct impact of pain on sexual motivation, yet high prevalence of reduced sexual desire in chronic pain populations (Basson et al., 2010; Fine, 2011) suggest that pain may adversely influence sexual motivation.

It's not exactly true that “No clinical data exist on the direct impact of pain on sexual motivation...” (as we'll see later), but first let's take a look at the actual study.1

Pairs of vigorously mating mice were assigned to either male “open field” or female “paced mating” situations, which mimics their respective natural preferences. One member of each pair was injected with a pain-inducing inflammatory compound (zymosan A or λ-carrageenan) into their genital or nongenital (hind paw, tail, cheek) regions. Sexual behavior was measured by mounting in open field (for males) or in paced mating (for females) conditions. In the latter situation, the smaller females could run into their safe room to avoid the males. 

The results generally indicated that the females hid from the males when injected with painful substances (Fig. 1A), but the males were not bothered (based on the total number of mounts) with the exception of a non-significant decline when the penis was injected with zymosan (Fig. 1C).

Fig. 1 (modified from Farmer et al., 2014). Reduction of sexual behavior in female but not male mice by inflammatory pain. A. Decreased mounting behavior in a paced mating paradigm when female mice receive zymosan (ZYM) or carrageenan (CARR) injections to the vulva, hind paw, tail, or cheek, compared with uninjected female mice (No Inj.). Bars represent mean ± SEM mounts with (shaded) or without (open) intromissions. C. No decreases in mounting behavior in an open field when male mice are treated in a similar fashion. *p < 0.05, **p < 0.01 compared with vehicle [NOTE: using uncorrected t-tests].

[As an aside, one could imagine that the mating behavior of human males might be more greatly affected by penile injections of any sort, and by inflammogen injections into the hand or cheek than what we're seeing here in the male mice.]

In addition to mounts, Table 1 in Farmer et al. lists 8 other behaviors × 2 treatments. Of these 16 comparisons to the vehicle control, five indicated reductions and one indicated an increase in activity of some sort, meaning that certain behaviors (number of ejaculations, latency to first mount, number of crossings to the male side, latency to return to the male side) were unaffected by one or both treatments [NOTE: using Dunnett's post-hoc comparisons that do correct for multiple comparisons]. Make of that what you will.

However, the pained females did indeed spend significantly less time in their male partner's side of the apparatus.

Next, some of the pained female mice were given pregabalin (Lyrica), an anticonvulsant drug used to treat neuropathic pain (kindly provided by one of the study sponsors, Pfizer). You'll be comforted to hear that analgesic administration and concomitant pain relief will lead to increased sexual activity in injured female mice (and probably in injured creatures of any sort).

On the other hand, administration of the non-selective dopamine agonist apomorphine, which is “pro-sexual” in mice but strongly emetic in humans, is unlikely to be welcomed by women as an antidote to a pain-quashed libido. Apomorphine (not related to morphine) is sometimes given to Parkinson's patients, but always in conjunction with other drugs to prevent vomiting. In fact, apomorphine is so unpleasant to humans that it has been used for aversion therapy in gay people (an “anti-sexual” agent if there ever was one).

Anyway, it was interesting to learn that rodents do not vomit, and that apomorphine reverses the pain-induced reduction in sexual behavior exhibited by female mice. This was interpreted to mean that sexual motivation was enhanced. But since apomorphine also increases locomotion in rodents, I wonder if other appetitive behaviors were enhanced as well.

The other pro-sexual drug used in the current study was melanotan-II, which is converted to the melanocortin-3/melanocortin-4 receptor agonist, bremelanotide (formerly known as PT-141, developed by Palatin Technologies). Intranasal bremelanotide underwent clinical testing to treat sexual dysfunction in humans (male and female), but trials were halted in 2008 because of untoward elevations of blood pressure in some individuals.

When given to injured female mice, melanotan-II reversed the reduction in sexual behavior. Unlike apomorphine, however, melanotan-II: (1) does not increase locomotion, and (2) is undergoing further testing in humans via a subcutaneous route of administration that doesn't increase blood pressure. Moreover, the authors are highly aware of their potential animal model:
Thus, the reversal of pain-induced reductions in female-paced sexual behavior likely reflects an enhanced incentive value of the paced mating context, indicating that motivational mechanisms can overcome the effects of pain. We suggest that restoration of pain-induced loss of libido may provide a more sensitive test of prosexual drugs than current paradigms. 2

According to the highly reputable Men's Journal, a co-author on the current paper, Dr. Jim Pfaus, is “arguably the world's preeminent expert on bremelanotide.” The 2009 magazine article states:
...Originally developed as a self-tanning agent, the drug had been repurposed when male study subjects reported a surprising side effect: erections.   ...

Pfaus showed me stunning testimonials from human test subjects. "On the five-point scale, I would rate the erection I had as a six," said one of the 1,300 anonymous testers. "You get this humming feeling," said another. "You're ready to take your pants off and go."

The drug worked equally well on women, who chronicled "an intense arousal" that lasted from six to 72 hours. "I was focused on sex," said one of the women.

However, the pesky side effects of increased blood pressure (in some men) and nausea (in one third of the women) were still an issue. That didn't stop the black market bremelanotide distributors.
But was it safe? "Well," says Pfaus, "we never resolved that blood pressure thing. There's no guarantee of purity. The FDA won't regulate it."

Five years later, Palatin has its subcutaneous version of bremelanotide in Phase 2B clinical trials for Hypoactive Sexual Desire Disorder (poster PDF) and other Female Sexual Dysfunctions (poster PDF). HSDD is a controversial diagnosis, discussion of which is beyond the scope of this post. 3

The media furor over the “not tonight, dear, I have a headache” evolutionary interpretation of sexual behavior in mice has completely overshadowed the potential drug marketing angle.

The Media Frenzy

Pain can kill ‘women’s sex drive’ but not men’s screams one headline. Not tonight dear, I have a headache: science behind the excuse: “Chronic pain diminishes a woman's sexual desire but has no impact on a man's, according to a study published in the journal of Neuroscience,” claims The Telegraph. 4

Quite obviously, no humans were tested by Farmer et al., 2014 and yet even the McGill press release plays up that angle, assisted by helpful quotes from the senior author:
“Not tonight, dear, I have a headache.” Generally speaking, that line is attributed to the wife in a couple, implying that women’s sexual desire is more affected by pain than men’s.

Now, researchers from McGill University and Concordia University in Montreal have investigated, possibly for the first time in any species, the direct impact of pain on sexual behaviour in mice.  ...

“We know from other studies that women’s sexual desire is far more dependent on context than men’s – but whether this is due to biological or social/cultural factors, such as upbringing and media influence, isn’t known,” says Jeffrey Mogil, a psychology professor at McGill and corresponding author of the new study. “Our finding that female mice, too, show pain-inhibited sexual desire suggests there may be an evolutionary biology explanation for these effects in humans – and not simply a sociocultural one.”

I've written at length about whether animal models of sexual problems are appropriate stand-ins for the human condition:
Which brings us to animal models for what we typically regard as profoundly human states: longing, angst, futility.  Or Desire, Dread, and Despair. The words don't easily lend themselves to rodent analogues, because they remind us of an unrequited crush or an existential crisis...

The animal models of these states are more mundane and less abstract, yet important for potentially explaining the neural mechanisms underlying human suffering: addiction, anxiety, and depression. But are they really adequate stand-ins for the human condition? Of course not. My purpose here isn't to critique animal research, but rather to consider actual behaviors and how they map onto the terminology used to describe them.

Does the model of pain-induced reduction of sexual behavior in female mice hold up in humans? The claim is that a lack of sexual motivation (or libido, if you will) is the inhibiting factor, rather than the pain itself.

Real Pain in Real Humans

How does chronic pain affect human sexual behavior? Is there a pronounced difference between men and women in terms of responsiveness? Is it true that this topic has never been studied?

One survey of 327 chronic pain patients (Ambler et al., 2001) found few differences between men and women:
Seventy-three percent of respondents had pain-related difficulty with sexual activity; most had several, in various combinations of problems with arousal, position, exacerbating pain, low confidence, performance worries, and relationship problems. ... There were few differences between men and women, and only weak relations emerged between specific problems and mood and disability.

Furthermore, it wasn't easy to attribute the problems to reduced libido or to physical limitations, as there wasn't a simple relationship between primarily physical and primarily psychological issues and overall physical, psychological, and emotional health.

Several other studies have examined sexual function specifically in patients with arthritis, a chronic pain condition. van Berlo et al. (2006) analyzed surveys from 271 patients with rheumatoid arthritis and found that men felt less sexual desire, while women masturbated and fantasized less often than controls. However, the patients did not report a difference in sexual satisfaction (although we don't know about the 77% who did not return the questionnaire).

An earlier study examined the effects of osteoarthritis of the hip joint on sexual activity (Currey, 1970). The author mailed a questionnaire to 235 potential patients and received replies from 121. He found that sexual problems were more commonly reported in women, but this was literally caused by stiffness and pain. A decline in sexual motivation was not the primary factor. In fact, the causes of sexual difficulty (i.e., interfering with heterosexual intercourse) did not differ between men and women. For women, it was pain in 49%, stiffness in 76% and loss of libido in only 20%. For men, those numbers were 50%, 75% and 27%.

So much for bremelanotide in female patients with chronic pain...

You may complain about demand characteristics and biased samples among those who complete and return surveys about sexual behavior, even when anonymous. Mice are so much simpler, they're not embarrassed to talk about it, they're not influenced by how their partner or doctor may react. Male mice are not less inclined to report sexual problems because they might be perceived as less macho. And female mice don't become sexually disinterested if their husbands are inconsiderate at any number of levels.

Oh wait, those are all sociocultural factors, which simply cannot explain the flighty female libido.

Further Reading

Of Mice and Women: Animal Models of Desire, Dread, and Despair

Lybrido for Low Libido?

How to Measure Female Desire

Underwear Models and Low Libido

Media HSDD: "Hyperactive Sexual Disorder Detection"

The Joy of Melanocortin Receptors


1 DISCLAIMER: Note that I am not an expert in mouse sexual behavior, so I am not qualified to critique the study on those grounds. I recognize that the present experiments represent a huge amount of work that builds upon a body of research by established investigators.

2 “The authors declare no competing financial interests.”

3 As I've written previously:
Hypoactive Sexual Desire Disorder (HSDD) is a controversial diagnosis given to women who have a low (or nonexistent) libido and are distressed about it. Dr. Petra Boynton has written extensively about the problematic aspects of the HSDD diagnosis and the screening tools used to assess it, as well as the medicalization of sexuality for pharmaceutical marketing purposes.
4 But Were the Experimenters Male or Female? Another study by the same research team received even more press coverage: the finding that male experimenters stress out laboratory rodents to a much greater extent than female experimenters. However, we don't know whether the animal handlers in the present study were male, female, or both.

ADDENDUM May 5 2014: Bethany Brookshire has a fantastic summary of that study, You smell, and mice can tell. A closer examination of the author contributions on the Farmer et al. paper suggests that the majority of investigators handling the mice (perhaps 10 out of 11) were female.


Ambler N, Williams AC, Hill P, Gunary R, & Cratchley G (2001). Sexual difficulties of chronic pain patients. Clinical Journal of Pain, 17 (2), 138-45 PMID: 11444715

Currey HL. (1970). Osteoarthrosis of the hip joint and sexual activity. Ann Rheum Dis. 29:488-93

Farmer, M., Leja, A., Foxen-Craft, E., Chan, L., MacIntyre, L., Niaki, T., Chen, M., Mapplebeck, J., Tabry, V., Topham, L., Sukosd, M., Binik, Y., Pfaus, J., & Mogil, J. (2014). Pain Reduces Sexual Motivation in Female But Not Male Mice Journal of Neuroscience, 34 (17), 5747-5753 DOI: 10.1523/JNEUROSCI.5337-13.2014

van Berlo WT, van de Wiel HB, Taal E, Rasker JJ, Weijmar Schultz WC, van Rijswijk MH. (2007). Sexual functioning of people with rheumatoid arthritis: a multicenter study. Clin Rheumatol. 26:30-8.

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At May 04, 2014 9:23 PM, Anonymous Anonymous said...

This study makes me want to inject painful inflammatory chemicals into the genitals of the researchers.


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