Research in pain from the lab of Jeffrey S. Mogil and McGill University has been making the news for some time. An April 28 press release from McGill reported that mice and rats appear to be more stressed when male researchers are around than when the researchers are female. In another study the McGill press release announced that: “Pain curbs sex drive in female mice, but not in males.” Recent research from McGill, along with various other institutions, was announced as: “Groundbreaking pain research.” Of course, all of this research was conducted in rodents, which raises the question of applicability to humans.
Rodents and other animals can be successfully used in research and in science in general in specific areas. For example, the fundamentals of physiology can be discovered using pretty much any mammal. Of course, comparative studies, studies that reveal differences among mammals, are also performed using various species by definition. This fact illustrates the problem. Even when many underlying processes are conserved among species, or general morphology is preserved, seemingly small genetic differences turn out to be very important. This is well known among animal modelers even though they obfuscate and do everything else they can in order to communicate the fabrication that these facts are immaterial. Even the April 28 press release starts out stating: “Scientists’ inability to replicate research findings using mice and rats has contributed to mounting concern over the reliability of such studies.”
Perhaps the best critique of pain research using animals comes from Mogil himself in Nature Reviews Neuroscience:
Many are frustrated with the lack of translational progress in the pain field, in which huge gains in basic science knowledge obtained using animal models have not led to the development of many new clinically effective compounds. A careful re-examination of animal models of pain is therefore warranted. Pain researchers now have at their disposal a much wider range of mutant animals to study, assays that more closely resemble clinical pain states, and dependent measures beyond simple reflexive withdrawal. However, the complexity of the phenomenon of pain has made it difficult to assess the true value of these advances. In addition, pain studies are importantly affected by a wide range of modulatory factors, including sex, genotype and social communication, all of which must be taken into account when using an animal model.
Mogil, Davis and Derbyshire similarly stated in Pain:
Basic scientific understanding of pain processing and modulation has greatly increased over the past few decades. However, our knowledge of the intricate molecular, cellular, and systems organization of nociception remains substantially incomplete. Furthermore, the management of pain in both acute and especially chronic settings remains far from optimal. Although the pharmaceutical industry has made substantial investments in analgesic drug development, a paucity of analgesics acting at novel molecular targets have been approved. Also lacking are new, more effective surgical targets and behavioral strategies for pain control, despite the clear need to improve upon the relatively modest efficacy of current treatments for many chronic pain conditions. This unfortunate state of affairs – whether accurate or simply ‘‘looking at the glass half empty” – has engendered considerable cynicism in the value of the animal models of pain that are currently at the core of the research and drug development enterprise. Simultaneously, new options have presented themselves in pain research using humans as subjects. The number of pain-related neuroimaging studies on human volunteers and patients has exploded, and there is increased interest in complementary human experimental techniques including quantitative sensory testing, microdialysis, epidemiology, physiology (e.g., nerve conduction studies), ex vivo studies of human cells and tissues, and both DNA- and RNA-based genetic studies. The perceived failure of animal studies for analgesic drug development and the increasing interest in human-based techniques has led some to call for the replacement of animal pain experiments with human volunteer studies.
However Mogil et al. end by stating: “We believe this would be a grievous mistake. The following represents a case for the continued reliance on, and necessity of, animal models in pain research.”
The perception of pain has commonalities among species. The mere fact that the basis for the animal rights philosophy is sentience means that animals and humans perceive pain and do so by similar mechanisms that we can study and appreciate. But the contribution of animals to relieving pain in humans is limited due to very small differences among species. Similar is not close enough when it comes to medicine. Moreover, the study of pain and the application of diagnostic and therapeutic modalities for humans are limited by the differences in pain pathophysiology and perception between men and women.
Men and women present differently when experiencing a myocardial infarction. Canto et al discovered that 42% of women experiencing a myocardial infarction did not report the classic symptoms of heart attack such as pain in the left arm, chest pain, or chest tightness. Women were more likely to report pain in the back or jaw, lightheadedness, shortness of breath, nausea and vomiting. If men and women report, and respond so differently to, the same pathophysiology, what are the odds that science can find the answer to reducing pain in humans by studying rodents? As I have discussed numerous times, there are differences among ethnicities, between the sexes, and even among strains of mice in terms of how individuals respond to drugs and disease.[7-10] And yet, despite these known differences, scientists still receive hundreds of millions in grant funding to study pain in rodents in hopes of helping humans.
Enna and Williams state:
In therapeutic areas as diverse as pain (Rice et al., 2008), stroke (O'Collins et al., 2006), neurodegeneration (Lindner, McArthur, Deadwyler, Hampson, & Tariot, 2008), and substance abuse (Gardner, 2008), numerous agents that displayed substantial efficacy and safety in animal models, have failed in the clinic (Hackam & Redelmeier, 2006). Similarly, animal models used to interrogate the PK and PD effects of NCEs are in need of further refinement so they have predictive value with regard to human use. . . . The studies with NK1 receptor antagonists, typified by aprepitant (MK-869), are a prime example of this phenomenon. Thus despite robust preclinical results, several members of this compound class failed to display efficacy in the clinic, leading to a debate about the relationship between a role of NK1 in mediating pain in humans (Hill, 2000) and the drug-like properties of the first-in-class NCEs used that may have precluded them reaching their intended site of action (Laszlo & Fox, 2000). Subsequent studies (Bergstrom et al., 2004) using PET imaging demonstrated that aprepitant occupied NK1 receptors in the CNS, leading to the conclusion that NK1 was not associated with pain behaviors in humans (Whiteside et al., 2008), thus providing a rationale as to why the animal models in this instance had no predictive value with regard to this target approach. Other examples of a disconnect between animal data and human responses include α4Β2 nicotinic agonists, like tebanicline (ABT-594) (Bannon et al., 1998). In this case, an NCE that was some 200 times more potent than morphine in various animal pain models had limited clinical efficacy due to side effects that were not detected in animal studies (Rueter, Honore, & Bitner, 2006). Moreover, clinical trials have indicated that the analgesic utility of TRPV1 antagonists, like SB-705498, are limited by effects on core temperature regulation (Caterina, 2008).  (See original for references)
Mogil ended his pro-vivisection article in Nature Reviews Neuroscience by stating:
One final point is that analgesic drug development requires not only valid and reliable models of efficacy, but also valid and reliable models of toxicity, so that therapeutic indices might be accurately estimated. Some might argue that common behavioural assays designed to detect drug side effects (for example, the rotarod test of ataxia) are even more subtle, difficult to interpret and in need of advances in sophistication.
Let me be clear. More sophisticated animal models will not have predictive value for human response to pain or medications designed to reduce pain. Animals and humans are examples of evolved, complex systems and thus the way one responds to a perturbation such as a drug or disease has no predictive value for another. We have explained why this is the case in numerus publications including: “Questions regarding the predictive value of one evolved complex adaptive system for a second: exemplified by the SOD1 mouse.”  Trans-Species Modeling Theory (TSMT) states:
While trans-species extrapolation is possible when perturbations concern lower levels of organization or when studying morphology and function on the gross level, one evolved complex system will not be of predictive value for another when the perturbation affects higher levels of organization.
TSMT is largely accepted by the two scientific communities that gave rise to it: evolutionary biology and complexity science. The one field that refuses to acknowledge the implications of being an evolved, complex system is the one that profits from using animals in a way that is inconsistent with TSMT: basic biomedical researchers that use animals.
Future generations, when paying off America’s debt, will ask why we spent the money we did in the fashion we did. The answer to that question with regards to pain research in rodents will not be flattering to our generation.
(Image courtesy of WikipediaCommons)
1. Sorge, R.E., et al., Olfactory exposure to males, including men, causes stress and related analgesia in rodents. Nat Methods, 2014. http://www.ncbi.nlm.nih.gov/pubmed/24776635
2. Greek, R. and N. Shanks, FAQs About the Use of Animals in Science: A handbook for the scientifically perplexed. 2009, Lanham: University Press of America.
3. Greek, R. and M.J. Rice, Animal models and conserved processes. Theoretical Biology and Medical Modelling, 2012. 9(40). http://www.tbiomed.com/content/9/1/40/abstract
4. Mogil, J.S., Animal models of pain: progress and challenges. Nat Rev Neurosci, 2009. 10(4): p. 283-94. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19259101
5. Mogil, J.S., K.D. Davis, and S.W. Derbyshire, The necessity of animal models in pain research. Pain, 2010. 151(1): p. 12-7. http://www.ncbi.nlm.nih.gov/pubmed/20696526
6. Canto, J.G., et al., Association of Age and Sex With Myocardial Infarction Symptom Presentation and In-Hospital Mortality. JAMA: The Journal of the American Medical Association, 2012. 307(8): p. 813-822. http://jama.ama-assn.org/content/307/8/813.abstract
7. Belmaker, R., Y. Bersudsky, and G. Agam, Individual differences and evidence-based psychopharmacology. BMC Medicine, 2012. 10(1): p. 110. http://www.ncbi.nlm.nih.gov/pubmed/23016518
8. Blair, E., Predictive tests and personalised medicine. Drug Discovery World, 2009(Fall): p. 27-31.
9. Dolgin, E., Big pharma moves from 'blockbusters' to 'niche busters'. Nat Med, 2010. 16(8): p. 837. http://dx.doi.org/10.1038/nm0810-837a
10. Hudson, K.L., Genomics, Health Care, and Society. New England Journal of Medicine, 2011. 365(11): p. 1033-1041. http://www.nejm.org/doi/full/10.1056/NEJMra1010517
11. Enna, S.J. and M. Williams, Defining the role of pharmacology in the emerging world of translational research. Advances in pharmacology, 2009. 57: p. 1-30. http://www.ncbi.nlm.nih.gov/pubmed/20230758
12. Greek, R. and L.A. Hansen, Questions regarding the predictive value of one evolved complex adaptive system for a second: exemplified by the SOD1 mouse Progress in Biophysics and Molecular Biology, 2013. http://www.sciencedirect.com/science/article/pii/S0079610713000539