Invertebrate pain and suffering: What do analgesic studies tell us?

by Timothy Chan16 min read22nd Sep 20213 comments

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Invertebrate welfarePain and sufferingWild animal welfare
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Disclaimer:

·         While this essay discusses methods and results of non-human animal experiments, I do not necessarily support non-human animal experimentation.

·         I wrote most of this in 2020 so some updates are probably missing.

·         I did not investigate all types of invertebrates.

·         I missed studies involving other types of analgesics.

·         I am not an expert in analgesics or invertebrate pain or the intersection of these fields.

·         The conclusions we make about topics in the philosophy of mind seem highly dependent on intuitions, and your intuitions may vary (from my own).

·         Problems in scientific research and publishing are not uncommon so the results of a specific experiment could be questionable. However, the chances of all results being wrong seems low, and I think the overall picture is accurate.

Summary

Wild animals face predation, hunger, disease, and many other challenges. Most wild animals are invertebrates. There is also a rising interest in forming invertebrates for human consumption. Scientific evidence suggests human-effective and vertebrate-effective analgesics have effects for, at least, types of invertebrates such as insects, crustaceans, snails, and different types of worms, suggesting that we should increase our credence that these animals can suffer. While there are studies that suggest some specific analgesics are not effective in these invertebrates, they seem to not strongly suggest a lack of pain because they do not rule out other possible differently implemented mechanisms (more discussion below). Overall, while effective analgesics can be considered evidence towards invertebrate pain, according to some, responses to noxious stimuli already seem sufficient for us to think that it likely exists. Even if one is not convinced, the large cost of being wrong about invertebrate pain may motivate us to care about invertebrates regardless.

Introduction

There are many wild animals who face predation, hunger, disease, and many other challenges. Most wild animals are invertebrates and may produce large numbers of offspring who die shortly after birth. In addition, there is a rising interest in forming invertebrates for direct human consumption. While many humans (as of 2021) seem to accept the idea that vertebrates are sentient, there is still controversy as to whether invertebrates can suffer. This essay summarizes studies involving the use of analgesics (painkillers) in invertebrates for evidence that helps us determine whether invertebrates can suffer, which would be relevant when considering the suffering of animals in the wild.

We cannot experience what other minds experience, and so we can never definitively prove nor disprove the idea that invertebrates feel pain (we can also neither definitively prove nor disprove the idea that other humans feel pain). Regardless, identifying in invertebrates what we consider the functional characteristics of pain or evidence of such functional characteristics, might suggest to some intuitions, that (subjective) pain accompanies (objective) nociception in invertebrates, and that observable behavioural consequences of analgesics result from physical operations that correspond to subjectively experiencing less pain.

One argument (by analogy) could be:

  1. Analgesics inhibit a subjective experience of pain while diminishing an observable nociceptive response in humans and other vertebrates.
  2. As in humans and other vertebrates, administration of analgesics to invertebrates can diminish the observable response to noxious stimuli.
  3. By analogy, analgesics decrease the subjective feeling of pain in invertebrates.
  4. And so, invertebrates can feel pain.

Analgesia vs. general anaesthesia

Evidence from studies of vertebrate-, or human-effective analgesic-affected invertebrates argues for the presence of pain in invertebrates through the functional analogy outlined above. Relevant studies can generally be categorized into two types: (1) studies that demonstrate whether these analgesics are able to inhibit the responses to noxious stimuli in invertebrates, but do not exclude the possibility of a general inhibition of responses (e.g., general anaesthesia), and (2) studies that attempt to find out whether these analgesics specifically inhibit the response to the noxious stimulus instead of producing a general non-specific inhibition of responses (e.g., general anaesthesia).

Studies of the first type are more common, and many may have been conducted with the goal of confirming the presence of opioid systems within animals – not necessarily to demonstrate the possibility of pain. A criticism of the results of these studies is that the purported analgesics are not in fact analgesics but instead act as general anaesthetics that inhibit responses in general, and hence inhibit the response to noxious stimuli along with other responses.

According to some intuitions (that I largely do not share), this criticism suggests animals might not be experiencing less pain and instead might only be responding less acutely. Due to this, some would argue that studies of the first type suggest only weaker evidence for pain and its inhibition in animals.1 Some studies (belonging to the second type) potentially avoid this criticism through alternate methodologies. Some of these studies will be discussed.

However, according to other intuitions (that I largely do share), we have strong evidence of pain inhibition from the fact that such specific vertebrate-effective, or human-effective analgesics can cause similar observable effects of reducing responses to noxious stimuli.

Insects

Honeybees, cockroaches, praying mantes, ants, and crickets have been subjects of experiments testing the effect of opiate agonists and antagonists on nociception and pain. Crickets take longer to escape a heated box with more morphine. In addition, though perhaps not directly related to acute pain, crickets can be addicted to morphine following long-term use.2 Praying mantes display a ‘frightening reaction’ in response to electric shocks, and the voltage threshold (a measure of tolerance) for this reaction can be increased by higher doses of morphine hydrochloride.3 Morphine-treated cockroaches take longer to move away from a hot area.4 And as in crickets, ants can be addicted to morphine – seeking it without an accompanying food reward. Interestingly, dopamine plays a role in this addiction response, which is analogous to aspects of opioid action in mammals.5

Honeybees react similarly to morphine and morphine hydrochloride to produce a dose-dependent reduction in defensive stinging response to electric shock. However, results from one self-administration study questioned the effectiveness of morphine in specifically inhibiting honeybee nociceptive responses. Amputated honeybees sought out pure sucrose solution as well as sucrose solution with morphine included, without significant preference for either, indicating no preference for morphine itself. The authors of this self-administration study concluded that further evidence is needed to answer the question of pain experiences in honeybees.6

Other studies may provide more conclusive evidence on the possibility of insect pain. Fruit flies injected with 3-aminopropyl(methyl)phosphinic acid (3-APMPA), an analgesic effective in rats, can pass through a heat barrier with a light source (attractive to fruit flies) or an elevated location (fruit flies prefer climbing) on the other side. Fruit flies with higher 3-APMPA dosage passed through the heat barrier more often. Increased movement would not be expected from general anaesthesia, while passing through more suggests a higher tolerance for high heat, which can be expected from analgesia.7 Hence, this study avoids the criticism that a decreased nociceptive response may be due to general anaesthesia instead of being due to analgesia, which may be stronger evidence of inhibited pain for some intuitions. Flies passing through a heat barrier could suggest a decision-making process where preferences to move towards light and elevated places are weighted against the unpleasant (or neutral, due to analgesia) presence of high heat under different levels of analgesic, and one stimulus is prioritized over the other.

Aside from analgesics for acute pain, human-effective analgesics for chronic pain (anti-neuropathics) may also be effective in fruit flies. Following nerve injury, fruit flies may become more sensitive to heat, i.e., they can be affected by temperatures not high enough to affect uninjured flies. Administration of the gabapentinoids gabapentin and pregabalin protected injured flies from oversensitivity to heat.8 Gabapentinoids treat oversensitivity in human patients with chronic pain. This may suggest the possibility of chronic pain in injured fruit flies.

Crustaceans

Prawns under the local anaesthetic benzocaine less frequently groom antennas exposed to sodium hydroxide and to acetic acid (pH extremes). Their reduced sensitivity did not accompany a change in swimming activity, and the authors suggest this indicated that instead of a general anaesthesia that inhibits a wide range of responses and movements, the local anaesthetic specifically inhibited the pain caused by pH extremes.1,9 Yet, research on other decapod (an order of crustaceans that includes prawns) species finds that neither benzocaine nor even extreme pH affected behaviour. In other words, no antenna grooming was observed with application of the (potential) chemical irritants.1,10 It should be noted though that other evidence could suggest decapod pain – for example, despite the chemical insensitivity and unresponsiveness to benzocaine, the same research group finding negative results later report that crayfish (also a decapod) do respond aversely to high temperature.11

Mantis shrimps defend themselves more slowly against electric shocks on morphine, and this effect is reversible by naloxone, an opioid receptor antagonist.12 On morphine hydrochloride, the crab Chasmagnathus granulatus responds less acutely to electric shocks.1,13 On morphine, the crab Carcinus mediterraneus is less defensive against striking of an area between eyestalks.14 One experiment that aimed to test whether morphine has a specific analgesic effect, instead of a general anaesthetic effect, had shore crabs exposed to electric shocks in a dark shelter, but not in an area where they are exposed to light. All else equal, shore crabs should prefer dark shelters over bright shelters, but what was observed was that morphine inhibited their movement from a bright shelter to a dark shelter, which may be inconsistent with an analgesic effect, and may indicate that morphine provides a general anaesthesia instead. The authors question whether analgesia from morphine is an appropriate criterion for the evaluation of the potential of pain in crustaceans.15 Indeed, there exists some controversy surrounding what can be concluded about crustacean pain from analgesic studies.16,17 The authors suggest that in studying pain we should give more weight to general behaviour rather than responses to specific opiates, because specific details of response mechanisms may differ physiologically and morphologically, between vertebrates and invertebrates. The authors also reference behavioural studies that demonstrate these more general responses to noxious stimuli.15

Snails, roundworms, flatworms, and earthworms

Other morphine-responsive invertebrates include snails, roundworms, and flatworms (planarians). Multiple snail species take longer to escape a noxious heat stimulus under morphine. Once again, naloxone reverses this effect.18–20 Besides opioids, snails on the neuroactive steroid 3a-hydroxy-5a-pregnan-20-one (3A5P) respond less quickly to a hot surface.21 On morphine and morphine-6-glucuronide, pig roundworms do not respond as negatively to heat exposure.22 C. elegans also displays thermal avoidance, which can be inhibited by morphine. This effect is reversible by the opiate antagonists naloxone and CTOP.23 Planarians avoid light by rapidly swimming away from a light source. With a sufficient dosage of morphine, planarians swim more slowly or more erratically away from light. Planarians also display morphine dependence after continued usage. Following withdrawal from morphine, planarians crinkle and become immobile, even with light stimulation. The opioid receptor agonist DAMGO may also produce withdrawal effects.24

Use of opioid agonists and antagonists in research demonstrates the presence of opioid systems in earthworms.25,26 Earthworms possess endogenous opioids. Naloxone also affects the withdrawal reflex of earthworms toward touch.25,27 Another argument (by analogy) for pain in invertebrates could compare the physiological and morphological details of these systems in invertebrates and vertebrates, though it should be emphasized that divergence in such details need not suggest divergence in overall function and pain (more discussion below). However, it is also true that components of opioid systems are involved in many other processes besides analgesia. Studies suggesting the presence or absence of opioid systems in the many different phyla of invertebrates warrant a separate review.

How should we interpret negative results?

Positive results seem to either strongly or weakly suggest pain inhibiting effects, depending on one's intuitions. However, some studies mentioned above showed negative results, i.e., morphine/benzocaine did not display its usual effects on honeybees and some crustaceans (and some crustaceans seem to be unresponsive to extreme pH). Should we count this as strong evidence that invertebrates do not feel pain? My view is that no, this does not necessarily disprove pain and only suggests unresponsiveness to a specific analgesic, or a specific type of stimuli (or experimental errors or inappropriate experimental design). As some pain researchers note, if some invertebrates are unable to respond to a local anaesthetic that is effective in vertebrates, it might be due to physiological and morphological differences that affect low-level implementation details of pain. A lack of pain experiences is not necessarily the explanation. Not all analgesics that work in humans should be expected to work in invertebrates, so some studies finding no effect is not strong evidence for a lack of pain. Pain may still exist despite human-effective drugs not working in invertebrates.

It might seem odd to count positive and negative results differently, but upon reflection, to me at least, this is not a problem. The fact that some analgesics work suggests functional similarity – and from a functionalist perspective – mental similarity. The fact that some analgesics are ineffective does not rule out other mechanisms that can implement the same function. To illustrate with an analogy: finding a specific key that fits a lock, strongly suggests that the door with that lock can be opened. But the fact that that specific key does not fit some other lock on some other door, does not strongly suggest that that other door cannot be opened. We could consider other sources of evidence too. We could try another key, or we could knock and see if someone responds from inside.

Conclusions

Various invertebrate species display reduced aversion, escape, or defensive responses following administration of vertebrate-effective analgesics or local anaesthetics. Some studies attempt to test beyond a simple inhibition of response and, depending on one's intuitions, may more strongly suggest the possibility of pain and its inhibition. Physiological and morphological differences that modify the effect of drugs, affect interpretations of negative results. Some suggest that instead of studying the effects of analgesics like morphine for evidence of pain, general behaviour to noxious stimuli should be the focus, as it seems to more clearly indicate whether pain exists for invertebrates.15 Analogies in function can be used to argue that immediate responses to, and changes in behaviour in response to noxious stimuli in invertebrates, indicate pain in invertebrates. Analgesic studies can be informative additions to the study of invertebrate pain, but researchers must also consider the possibility of physiological and morphological differences when interpreting results.

Even if one is uncertain, a precautionary principle for animal welfare may motivate caring about invertebrates and treating them as beings that do suffer: “Where there are threats of serious, negative animal welfare outcomes, lack of full scientific certainty as to the sentience of the animals in question shall not be used as a reason for postponing cost-effective measures to prevent those outcomes”.28 Alternatively, utilitarians may consider invertebrate suffering, occurring in the wild or in human industry, as being largely negative in expectation and aim to reduce its disvalue.

 

Acknowledgments

Aaron Gertler and Max Carpendale provided useful comments.


 

Further reading

Do Bugs Feel Pain?

Invertebrate sentience: a review of the behavioral evidence

Invertebrate sentience: A review of the neuroscientific literature

Opioid Drugs, Part I: Mechanism of action

 

References

1.       Elwood, R. W. Pain and suffering in invertebrates? ILAR J. 52, 175–184 (2011).

2.       Zabala, N. A. & Gómez, M. A. Morphine analgesia, tolerance and addiction in the cricket pteronemobius sp. (orthoptera, insecta). Pharmacol. Biochem. Behav. 40, 887–891 (1991).

3.       Zabala, N. A. et al. Opiate receptor in praying mantis: Effect of morphine and naloxone. Pharmacol. Biochem. Behav. 20, 683–687 (1984).

4.       Gritsai, O. B., Dubynin, V. A., Pilipenko, V. E. & Petrov, O. P. Effects of peptide and non-peptide opioids on protective reaction of the cockroach Periplaneta americana in the ‘hot camera’. J. Evol. Biochem. Physiol. 40, 153–160 (2004).

5.       Entler, B. V., Cannon, J. T. & Seid, M. A. Morphine addiction in ants: A new model for self-administration and neurochemical analysis. J. Exp. Biol. 219, 2865–2869 (2016).

6.       Groening, J., Venini, D. & Srinivasan, M. V. In search of evidence for the experience of pain in honeybees: A self-Administration study. Sci. Rep. 7, 1–8 (2017).

7.       Manev, H. & Dimitrijevic, N. Drosophila model for in vivo pharmacological analgesia research. Eur. J. Pharmacol. 491, 207–208 (2004).

8.       Khuong, T. M. et al. Peripheral straightjacket (α2δ Ca2+ channel subunit) expression is required for neuropathic sensitization in Drosophila. Philos. Trans. R. Soc. B Biol. Sci. 374, (2019).

9.       Barr, S., Laming, P. R., Dick, J. T. A. & Elwood, R. W. Nociception or pain in a decapod crustacean? Anim. Behav. 75, 745–751 (2008).

10.    Puri, S. & Faulkes, Z. Do Decapod Crustaceans Have Nociceptors for Extreme pH? PLoS One 5, (2010).

11.    Puri, S. & Faulkes, Z. Can crayfish take the heat? Procambarus clarkii show nociceptive behaviour to high temperature stimuli, but not low temperature or chemical stimuli. Biol. Open 4, 441–448 (2015).

12.    Maldonado, H. & Miralto, A. Effect of morphine and naloxone on a defensive response of the mantis shrimp (Squilla mantis). J. Comp. Physiol. 147, 455–459 (1982).

13.    Lozada, M., Romano, A. & Maldonado, H. Effect of morphine and naloxone on a defensive response of the crab Chasmagnathus granulatus. Pharmacol. Biochem. Behav. 30, 635–640 (1988).

14.    Bergamo, P., Maldonado, H. & Miralto, A. Opiate effect on the threat display in the crab Carnicus mediterraneus. Pharmacol. Biochem. Behav. 42, 323–326 (1992).

15.    Barr, S. & Elwood, R. W. No evidence of morphine analgesia to noxious shock in the shore crab, Carcinus maenas. Behav. Processes 86, 340–344 (2011).

16.    Elwood, R. W. Evidence for pain in decapod crustaceans. Anim. Welf. 21, 23–27 (2012).

17.    Diggles, B. K. Review of some scientific issues related to crustacean welfare. ICES J. Mar. Sci. 76, 66–81 (2019).

18.    Kavaliers, M. & Hirst, M. Tolerance to the Morphine-influenced Thermal Response in the Terrestrial Snail Cepea Nemoralis. Neuropharmacology 22, 1321- (1983).

19.    Romero, S. M. B., Hoffmann, A. & Menescal-de-Oliveira, L. Is there an opiate receptor in the snail Megalobulimus sanctipauli? Action of morphine and naloxone. Comp. Biochem. Physiol. Part C Pharmacol. 107, 37–40 (1994).

20.    Achaval, M. et al. The terrestrial gastropoda Megalobulimus abbreviatus as a useful model for nociceptive experiments. Effects of morphine and naloxone on thermal avoidance behavior. Brazilian J. Med. Biol. Res. 38, 73–80 (2005).

21.    Kavaliers, M., Perrot-Sinal, T. S., Desjardins, D. C., Cross-Mellor, S. K. & Wiebe, J. P. Antinociceptive effects of the neuroactive steroid, 3α-hydroxy-5α- pregnan-20-one and progesterone in the land snail, Cepaea nemoralis. Neuroscience 95, 807–812 (1999).

22.    Pryor, S. C., Nieto, F., Henry, S. & Sarfo, J. The effect of opiates and opiate antagonists on heat latency response in the parasitic nematode Ascaris suum. Life Sci. 80, 1650–1655 (2007).

23.    Nieto-Fernandez, F. et al. The effect of opioids and their antagonists on the nocifensive response of Caenorhabditis elegans to noxious thermal stimuli. Invertebr. Neurosci. 9, 195–200 (2009).

24.    Dziedowiec, E. et al. Mu Opioid Receptor Agonist DAMGO Produces Place Conditioning, Abstinence-induced Withdrawal, and Naltrexone-Dependent Locomotor Activation in Planarians. Neuroscience 386, 214–222 (2018).

25.    Gesser, B. P. & Larsson, L.-I. Enkephalins may act as sensory transmitters in earthworms. Cell Tissue Res. 246, 33–37 (1987).

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28.    Birch, J. Animal sentience and the precautionary principle. 2, 1 (2017).

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3 comments, sorted by Highlighting new comments since Today at 12:59 PM
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Do analgesics also reduce reflexive responses to noxious stimuli in humans? If so, this might be an argument against them merely reducing responses to noxious stimuli at all being good evidence for conscious pain (effects on learning strengthens the argument somewhat, though). We'd want something that selectively targets the (consciously experienced) negative affect of pain in humans, but as far as I know, reflexive responses may be possible without negative affect (in humans and nonhumans).

That's an excellent point. If analgesics also reduce reflex responses towards noxious stimuli, then in some cases analgesics could be diminishing nociceptive responses while not inhibiting conscious (reportable) pain. 

I don't know much about how analgesics affect nociceptive reflexive responses in humans. According to the abstract of this study on non-human primates (haven't looked into the study in detail),  "depending on the dose, nociceptive reflexes [are] facilitated or inhibited" by morphine. So this possibility might prevent us from updating too much to "analgesics are preventing pain when they inhibit nociception" to the extent that the analgesics are inhibiting reflexive nociceptive responses.

One way this might not be an issue is if someone thinks consciousness is "smeared spatially and temporally" or if they think nested minds are possible. For them, through analogies in function, they might think the reflexive responses themselves could be in pain. But then again, there are probably fewer people who think like this than people who think invertebrates feel pain.

A related thought: 

Some humans are much less sensitive to physical pain.

1. Could an observer correctly differentiate between those with normal and abnormally low sensitivity to pain? 

2. For humans who're  relatively insensitive to pain, but still exhibit the appropriate response to harm signals (assuming they exist), would analgesics diminish the "appropriateness" of their response to a harm signal?