Animals in Research: A painful conundrum

May 21 2009 Published by under Animals in Research, Neuroscience

A recent article in Nature Reviews: Neuroscience by J. Mogil overviews animal models used in different kinds of pain research. (If you don't have access let juniorprof bring you up to speed on pain research.) The NRN review is motivated by what the author describes as a perception of frustration with the progress made to date in translating seemingly promising research to the human clinical treatment of pain. I don't know that I'd venture an opinion as to whether success has been good, bad or indifferent in this area- certainly there are many unsolved areas of pain management. Unsolved areas that cause unbelievable distress to individuals with attendant interference with their quality of life and vocational output. Nevertheless, the review puts on a good argument for the body of research using animals that has gone into our current understanding of pain and the ability we have to treat pain. It is worth a read.
Something that is worth discussion without being steeped in the pain research literature arises via a comment to the review that was written by A. D. Craig. [h/t: a reader who may or may not wish to self-identify]
A rat is not a monkey is not a human: comment on Mogil (Nature Rev. Neurosci. 10, 283-294 (2009))


The thesis of this commentary boils down to an assertion that animal models of human pain (or at least a subset of the subjective experiences grouped as pain) are insufficient because of species differences in brain structure and function.

One major reason why pain models in rodents have had little translational success that needs to be added to those mentioned in the article is that -- in addition to the numerous genetic and neurochemical differences between rodents and humans, even in the spinal dorsal horn -- rats and mice simply do not have the neuroanatomical pathway to the forebrain that is crucial for pain sensation in humans.

-snip-


In contrast to the situation for lamina I neurons, which can be studied in rodents (for example, see Ref. 20) because there are strong similarities (and also strong differences!) between rat and primate dorsal horns, the forebrain and the feelings of humans in pain cannot be studied in species that do not have the same neuroanatomical substrates. I submit that these points strongly recommend greater emphasis on studies of pain in humans.

What is fascinating here is that this is an example which would seemingly play right into the hands of the critic of animal research. Aha! Animal research cannot possibly contribute if the circuits are absent! Of course, the situation is complicated and clearly Craig is referring to only one subgroup of the investigations into things we group under the single descriptor of pain. The original review makes the breadth of phenomena and biological contributors to the experiences of pain fairly clear. It is also the case that even Craig refers to the fact that there may be some slight controversy to his substantive points about neurological architecture.
However, if we credit Craig's points for argument's sake it leads to another and more general observation about animal models. This passage is particularly striking.

Finally, and perhaps of the utmost significance, the re-representation of this pathway in the anterior insular cortex is crucial for subjective feelings of pain (or any other feeling) in humans and neither rodents nor monkeys seem to have a homologous structure. The inescapable truth is that pain in humans is indeed a subjective experience. The available evidence indicates that neither rodents nor monkeys can experience feelings in the same way that humans do.

One of the points of factual debate* between the animal research and ARA perspectives on the use of animals in research is on the capacity of animals to feel pain. Also the capacity to suffer which, although undefined in most cases, we might assume ties into the type of subjective experience that Craig is trying to delineate from primary tactile experiences of pain. You can think of your favorite points of debate in this area but IME in the more productive versions, the anti-animal research perspective asserts that animals are in "pain and distress" from some particular research protocol. The animal research side (and I am not just talking bull sessions in the cafe; serious investigation goes into making regulation and policy based on these questions) replies with an attempt to define measures that might reflect pain and distress and then to do studies to see if a particular research protocol leads to increases in those measures of pain and distress.
In those cases where the answer comes back "No, we cannot observe anything about this animal that is consistent with an increase in pain and distress", sometimes the counter-argument is raised that scientists and veterinarians simply do not look at the right measures and there must really still be an increase. Why? Because through the technique of introspection the AR supporter has confidently concluded that what would be painful and/or distressful for him or herself must necessarily be painful and distressful to a rat.
Craig's commentary seriously questions this confidence. If he is correct in his analysis of the data, it provides a very strong reason for why it is not viable to conclude that human introspection tells us much about the rodent experience of pain.
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*to the extent this every happens

9 responses so far

  • becca says:

    Is there a human who's had a stroke or some other neurological condition that causes this area of the brain to be inactive? Can we ask them what they feel?
    (I'm reminded of a House episode here, but I don't know if that was a realistic portrayal of such a condition).
    Also, pain and 'discomfort' are both important. I remember pulling out retinas on anesthetized rats. I know in my logic brain it didn't "hurt" them. But I honestly couldn't imagine it not scaring them. This could well be totally inaccurate projection (although since we do sometimes study fear and anxiety in animal models, I'd venture that we are modeling something akin to what we think of as fear, even if we could never recapitulate it exactly).

  • juniorprof says:

    Wow! I missed Bud Craig's commentary somehow... His points are well taken but we are ultimately arguing over terms, pain vs. nociception. We study pain in humans, we study nociception in animals. While the projections to brain centers may not be analogous in humans and rodents the peripheral nociceptors are similar and the lamina I neurons are likely more similar than they are dissimilar (I hope everyone can appreciate what a complex problem it would actually be to look at this in great detail).
    It bugs me somewhat that while Bud Craig does refer to the evidence that these pathways and their ultimate termination are absent in rodents (and monkeys) that he fails to consider the notion that similar pathways are there but their integration is just different. How can you know this after all, it is still the case that you cannot ask the mouse how it feels right now (but one might note that Jeff Mogil's group has indicated that another mouse likely can, at least if they're acquainted -- see his group's Science paper on empathy and pain in mice).
    On your ARA point, its a very interesting argument, that any ARAer will readily ignore.

  • juniorprof says:

    Becca,
    How on earth are you going to scare an anesthetized animal? It was real anesthesia right, not the pretend kind.

  • DrugMonkey says:

    we are ultimately arguing over terms, pain vs. nociception. We study pain in humans, we study nociception in animals.
    Well, I think your latter assertion is the point at hand, no? Yes, we don't think that rodents or potentially other nonhuman animals experience the subjective, affective and distressing aspects of pain to the same extent as do human animals...and for good empirical reasons.
    But it is far from a finished debate. Particularly when those empirical reasons are not appreciated by all. This point of Craig's contributes substantially, imo. If the substrates by which the human brain produces the more distressing aspects are missing in another species, this puts another important plank in the interpretation that pain is different in that critical way for that species.

  • DrugMonkey says:

    Is there a human who's had a stroke or some other neurological condition that causes this area of the brain to be inactive? Can we ask them what they feel?
    Craig references many human studies in making his point. Some are of stroke but I didn't pour through exhaustively. I think perhaps this one is closest to your question?
    http://www3.interscience.wiley.com/journal/109678255/abstract?CRETRY=1&SRETRY=0

    Abstract
    We describe the behavioral and neuroanatomical features of asymbolia for pain occurring in 6 patients following unilateral hemispheric damage secondary to ischemic lesions in 5 and traumatic hematoma in 1. In the absence of priMarchy sensory deficits, these 6 patients showed a lack of withdrawal and absent or inadequate emotional responses to painful stimuli applied over the entire body, as well as to threatening gestures. Five patients also failed to react to verbal menaces. Patients appeared unconcerned about the defect and seemed unable to learn appropriate escape or protective responses. Common associated abnormalities were rapidly resolving hemiparesis, cortical-type sensory loss, unilateral neglect, and body-schema disorders. Neuroradiological examination disclosed left hemispheric lesions in 4 patients and right hemispheric involvement in 2. Although lesion extension differed, the insular cortex was invariably damaged in all 6 patients. These findings suggest that insular damage may play a critical role in the development of the syndrome by interrupting connections between sensory cortices and the limbic system.

  • becca says:

    Juniorprof- Probably you can't scare them; I did say this wasn't necessarily what I logically knew to be true.
    It was real anesthesia (ketamine/xylazine), but it didn't necessarily *look* like complete loss of consciousness from the external effects (and nobody was interested in explaining how the drugs work to a grad student). It wasn't easy to tell precisely when loss of consciousness occurred, and of course the rats still had their eyes open and reflexive muscle movement, and obviously they could breathe on their own.

  • juniorprof says:

    DM, I agree, my point is simply that nociception is a requisite for pain except in rare circumstances like the stroke patients that are referred to by Craig. Hence, I do not agree in terms of the failure of moving preclinical findings into clinical utility. And we shouldn't ignore recent successes, prialt (VGCaC inhibitor), neurontin (gabapentin), anti-NGF treatments, anti-IL-6 treatments, anti-TNF, etc., that moved on thanks to preclinical models.
    Then again, understanding the subjective pain experience in humans should certainly be a major aim of pain research and identifying targets that underlie distressing qualities of pain, depression co-morbidity, etc., may well require target validation work that is human specific if you want to do this without modifying nociception per se. On the other hand, agents that reduce nociceptive transmission may well achieve these effects as as a result of their primary action.

  • juniorprof says:

    It was real anesthesia (ketamine/xylazine), but it didn't necessarily *look* like complete loss of consciousness from the external effects (and nobody was interested in explaining how the drugs work to a grad student).
    You could measure loss of pupillary reflex, for instance, to check for level of sedation. Ketamine is an NMDA antagonist.

  • Paul Browne says:

    Drugmonkey"The original review makes the breadth of phenomena and biological contributors to the experiences of pain fairly clear. It is also the case that even Craig refers to the fact that there may be some slight controversy to his substantive points about neurological architecture."
    To be fair to Craig he also points out that "In contrast to the situation for lamina I neurons, which can be studied in rodents...because there are strong similarities (and also strong differences!) between rat and primate dorsal horns..." and his previous publications (e.g. 1,2) make it clear that we can learn a lot from studying nociception and pain and animal models. My understanding is that he is saying that you have to be sure that the aspect of nociception or pain that you are studying in animals is relevent to the pain pathways in humans, and that there are some aspects of pain that can (probably) only be studied in human subjects. If he is saying that I agree with him, though it is a pity that his words will be presented out of context by ARAs. Having said that I agree with juniorprof that he may be ovestating his case.
    juniorprof "It bugs me somewhat that while Bud Craig does refer to the evidence that these pathways and their ultimate termination are absent in rodents (and monkeys) that he fails to consider the notion that similar pathways are there but their integration is just different."
    While I find Craig's hypothesis about the role of the anterior insular cortex (AIC) and the von Economo neurons (VEN) it contains in consciousness in humans (and to a lesser extend apes, whales and elephants) fascinating I agree with you that it would be wrong to assume that similar pathways are not present in other species, even if they don't replicate all the functions of the VENs. After all many of the processes in which the AIC is implicated in humans, for example orgasm, also occur in animals which lack VENs.
    1) Craig A.D."Distribution of trigeminothalamic and spinothalamic lamina I terminations in the macaque monkey" J Comp Neurol. 2004 Sep 13;477(2):119-148. DOI:10.1002/cne.20240
    2) Craig A.D. "How do you feel? Interoception: the sense of the physiological condition of the body" Nat Rev Neurosci. 2002 Aug;3(8):655-666. DOI:10.1038/nrn894

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