Social Modulation of Pain as Evidence for Empathy in Mice

Abstract

Empathy is thought to be unique to higher primates, possibly to humans alone. We report the modulation of pain sensitivity
in mice produced solely by exposure to their cagemates, but not to strangers, in pain. Mice tested in dyads and given an identical
noxious stimulus displayed increased pain behaviors with statistically greater co-occurrence, effects dependent on visual
observation. When familiar mice were given noxious stimuli of different intensities, their pain behavior was influenced by
their neighbor's status bidirectionally. Finally, observation of a cagemate in pain altered pain sensitivity of an entirely
different modality, suggesting that nociceptive mechanisms in general are sensitized.

Full text

DOI: 10.1126/science.1128322
, 1967 (2006); 312Science
et al.Dale J. Langford,
in Mice
Social Modulation of Pain as Evidence for Empathy
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sidering the actually imposed changes in leg
length) that ants might run by as much faster on
stilts as they ran slower on stumps (0.48 m/s, a
value regularly observed in highly motivated
normal ants and almost reached by the fastest
ants on stilts). This procedure indeed yields a
value that is not significantly different from the
observed homing distances in ants on stilts
(open box in Fig. 3, A; 14.25 m, IQR 0 3.35 m),
thus confirming the consistency of our data with
the step integrator hypothesis.
The slower speeds of the ants walking on stilts
further rule out the only alternative explanation of
our homing distance data (Fig. 3A, solid boxes).
In principle, a step integrator and a time-lapse
integrator would both yield the same homing
distances, even in ants with manipulated leg and
stride lengths, if only the ants kept their stride
frequencies constant Eor in normal ants, walking
speed—which in fact they almost do under nor-
mal conditions (19, 20)^. Constant stride frequen-
cy would result in a change in walking speed in
proportion to altered stride length and a resulting
difference in homing distance during a set (out-
bound) travel time. This assumption is evidently
not correct, though, given the walking speeds of
the experimental animals.
Future studies will have to address the mech-
anism of the proposed step integrator, for
example, whether it actually registers steps by
means of proprioreceptors, or whether it inte-
grates activity of a walking pattern generator,
and to what extent sensory feedback regarding
stride length and walking performance is
considered.
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Supporting Online Material
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Materials and Methods
SOM Text
References and Notes
Movie S1
2 March 2006; accepted 26 May 2006
10.1126/science.1126912
Social Modulation of Pain as Evidence
for Empathy in Mice
Dale J. Langford, Sara E. Crager, Zarrar Shehzad, Shad B. Smith, Susana G. Sotocinal,
Jeremy S. Levenstadt, Mona Lisa Chanda, Daniel J. Levitin, Jeffrey S. Mogil
*
Empathy is thought to be unique to higher primates, possibly to humans alone. We report the
modulation of pain sensitivity in mice produced solely by exposure to their cagemates, but not to
strangers, in pain. Mice tested in dyads and given an identical noxious stimulus displayed increased
pain behaviors with statistically greater co-occurrence, effects dependent on visual observation.
When familiar mice were given noxious stimuli of different intensities, their pain behavior was
influenced by their neighbor’s status bidirectionally. Finally, observation of a cagemate in pain
altered pain sensitivity of an entirely different modality, suggesting that nociceptive mechanisms in
general are sensitized.
A
lthough most consider true empathy
to be an exclusive ab ility of higher
primates, empathy may be a phyloge-
netically continuous phenomenon with sub-
classes such as Bemotional contagion[ well
within the reach of all mammals (1). However,
there is little evidence for adult-adult empathy
outside of primates. In rats (2) and pigeons (3),
the pain-related distress of a conspecific can
serve as a conditioning stimulus. Rats produced
operant responses to terminate the distress of a
conspecific (4), but this might be better ex-
plained by arousal than altruism (5). One theory
of human empathy postulates Bphysiological
linkage[ between empathizing individuals (6).
In one study, empathic accuracy for negative
emotion was highest in those dyads featuring
high levels of time synchrony of autonomic
measures (7). We hypothesized that if empathy
does indeed exist in mice, the real-time ob-
servation of pain in one mouse might affect the
responses of its conspecifics to painful stimuli.
We first used a sensitive nociceptive assay,
the reflexive 0.9% acetic acid abdominal con-
striction (Bwrithing[) test. We placed mice
singly within transparent Plexiglas cylinders to
observe writhing behavior. For comparison, we
placed two same-sex mice within each cylinder
and injected either one or both mice. In the
Bboth writhing[ (BW) condition, each mouse
observed the other in pain; in the Bone writh-
ing[ (OW) condition, the injected mouse ob-
served an uninjected counterpart. BW mice
displayed significantly more pain behavior than
isolated mice, but only when their counterparts
were cagemates (Fig. 1A). The hyperalgesia was
marginally enhanced in same-sex siblings liv-
ing together, but a separate experiment con-
firmed that close genetic relatedness was not
required (fig. S1). Writhing behavior in BW
dyads co-occurred in time at levels significantly
exceeding those expected by chance (Fig. 1B)
and significantly more so in cagemate pairs
than stranger pairs. The hyperalgesia and be-
havior co-occurrence developed over 14 to 21
days of being housed together (Fig. 1, C and
D). In general, observed behaviors other than
writhing were similar across all conditions
(figs. S2 and S3), although evidence suggested
higher levels of anxiety or stress produced by
the noxious stimulus in stranger pairs relative to
cagemates (fig. S4). Because the observed ef-
fects on pain behavior were higher in cage-
mates, stress is not a likely mediator.
When strangers were tested in dyads, a sig-
nificant decrease in writhing behavior was ob-
served in the OW condition compared to that
observed in isolation (Fig. 1A). The inhibition
was entirely specific to males (fig. S5) and is
likely due to distraction or social stress–induced
analgesia.
These findings imply the communication of
pain from one mouse to another. To determine
the transmitting sensory modality, we blocked
sensory inputs individually, by placing physical
barriers to sight and/or touch or by rendering
mice anosmic or deaf (8). The only manipula-
tion that significantly abolished the BW/OW
hyperalgesia was a visual blockade using an
opaque Plexiglas barrier (Fig. 2A). EDespite their
albinism, the CD-1 mice used in these studies
display no deficits in visually dependent be-
havioral tasks (9).^ The opaque barrier also
Department of Psychology and Centre for Research on
Pain, McGill University, Montreal, QC H3A 1B1, Canada.
*To whom correspondence should be addressed. E-mail:
jeffrey.mogil@mcgill.ca
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blocked the co-occurrence of writhing behavior
in the BW condition (Fig. 2B). Zinc sulfate
treatment destroys the olfactory epithelium in
the mouse but spares axonal transport from the
vomeronasal organ to the accessory olfactory
bulb (10), and thus pheromonal communication
cannot be ruled out. It is, of course, highly
likely that the recognition of the other mouse in
the dyad as stranger, familiar, or sibling was
achieved via olfactory cues (11), which were
likely unimpeded by the barriers. Indeed, social
communication is recognized to be commonly
multimodal in many species (12).
An existing data set (13) provided an inde-
pendent verification of the social co-occurrence
of pain behavior in simultaneously tested mice,
in another assay. In the 5% formalin test, lick-
ing behavior was statistically time-synchronized
within runs of four mice tested individually in
Plexiglas observation cylinders, but in close
proximity and in full view of each other (figs.
S6 and S7A). The co-occurrence of pain be-
haviors in familiar individuals may itself be
evidence of empathy, representing a compelling
analog to the demonstrations of physiological
linkage in empathizing humans (7).
These formalin data also showed a reduction
of between-subject variance within a run (fig.
S7B), suggesting that subjects_ pain behaviors
were being influenced, perhaps bidirectionally,
by their neighbors. In a new experiment, we
compared pain behavior in Bboth licking[ dyads
in which both mice received either a high
dose (5%) or a low dose of formalin (1%), or in
which each mouse received different doses (1%,
5%). Pain behavior was influenced by that of
the neighbor mouse, such that licking times
were marginally increased in mice receiving the
low dose while observing a high dose–injected
cagemate, and significantly reduced in mice
receiving the high dose while observing a low
dose–injected cagemate (Fig. 3). No significant
effects were observed among strangers (fig. S9).
Finally, we investigated whether the obser-
vation of a cagemate in pain could modulate
sensitivity to pain of a wholly different modal-
ity. Mice were tested in dyads as described, but
in addition to measuring writhing behavior, we
tested all mice for their sensitivity to withdraw
from a noxious radiant heat stimulus before and
at 5-min intervals after injection of acetic acid
(or no injection). Injection and the mere ob-
servation of a cagemate_s writhing behavior
both produced significant and equivalent ther-
mal hyperalgesia (Fig. 4). No observation ef-
fects whatsoever were observed among strangers
(fig. S10). Concurrent thermal pain testing did
not abolish the BW/OW increase in writhing
behavior (Fig. 4C), and a significant correlation
was observed between the writhing behavior of
Fig. 1. (A to D) Mice injected with 0.9% acetic acid in the presence
of similarly injected cagemates display higher levels of pain behavior,
which co-occurs in time. In all graphs, group sample sizes are
indicated in italics. (A) Mice were tested in isolation (Isolated), or in
dyads where either one mouse (One Writhing; OW) or both mice
(Both Writhing; BW) received acetic acid injections. Bars represent
the mean T SEM percentage of sampled intervals showing writhing
behavior (% Samples Writhing). *P G 0.05, ***P G 0.005 by Dunnett
two-way case-control comparison posthoc test compared to Isolated
mice. (B) Statistically significant co-occurrence in writhing behavior
in the Cagemates and Strangers conditions (sign test, P G 0.05 in
both cases); the co-occurrence was significantly higher in Cagemates.
Using data from (A), the expected number of samples with writhing in
both mice of the dyad was calculated as a joint probability. Bars
represent the mean T SEM excess of observed samples with joint
writhing above the expected value, as a percentage. **P G 0.01
compared to Strangers (Student’s t test). (C) Data from a separate
experiment using naı
¨
ve mice housed together for 1, 7, 14, 21, or 28
days and tested in BW dyads. Isolated mice were taken from the 28-
day group, but were tested alone. Bars are as in (A). *P G 0.05 by
Dunnett one-way case-control comparison posthoc test compared to
Isolated mice. Data in (D) were calculated from subjects shown in
(C); symbols represent the mean T SEM excess of observed samples
with joint writhing above the expected value, as a percentage. *P G
0.05 compared to zero (sign test). Significant linear trends were
evinced in (C) and (D) (P 0 0.001 and P G 0.005, respectively).
Fig. 2. (A and B) Apparent dependence of socially mediated
hyperalgesia and co-occurrence on visual cues. Mice, all
cagemates (n 0 10 to 36 per group; housed together for 921
days), were tested in dyads as described in Fig. 1, such that
either one mouse (One Writhing; OW) or both mice (Both
Writhing; BW) received 0.9% acetic acid injections. ‘‘Control’’
data (intact mouse face cartoon) were taken from Cagemates
condition in Fig. 1 for purposes of comparison. (A) Bars
represent the mean T SEM percentage of sampled intervals
showing writhing behavior (% Samples Writhing). *P G 0.05 by
Student’s t test compared to OW group. The significantly lower
writhing behavior of the Deaf-OW group reflects the relative
insensitivity to the noxious stimulus of the BALB/c strain, as
previously reported (24). (B) The abolition of writhing behavior
co-occurrence in BW dyads in which one mouse is prevented
from seeing the other (Opaque condition). Bars represent the
mean T SEM excess of observed samples with joint writhing
above the expected value, as a percentage. **P G 0.01 compared to Control group (Student’s t test).
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one mouse in the dyad and the thermal hy-
peralgesia exhibited by the other (Fig. 4D). These
data suggest that the pain system is sensitized in
a general manner by the observation of pain in a
familiar, and furthermore demonstrate that so-
cially mediated hyperalgesia can be elicited in
the clear absence of imitation. Mechanisms un-
derlying these phenomena are thus more likely
to be found in the sensory/perceptual system than
in the motor system.
Rodents are known to recognize and have
emotional reactions to the pain of conspecifics
(2), and their pain sensitivity can be altered by
social factors (14–17). However, most of these
studies reported analgesia rather than hyper-
algesia and did not evaluate effects in real time,
when another_s pain was actually being ob-
served. These phenomena may represent an
example of coaction social facilitation, de-
pending on one_s definition of that term (18).
However, our findings are consistent with the
perception-action model of empathy proposed
by Preston and de Waal (1), both in the auto-
matic priming of somatic responses in a state
similar to that of the attended object and in the
modulating effects of familiarity and similarity
of experience between subject and object. Our
observations cannot be easily explained by stress,
imitation, or conditioning, and they neither de-
pend on nor necessarily indicate the presence of
sympathy, conscious (cognitive) representations,
or altruism. Empathy for pain is currently a topic
of much study in humans (19–21), and Bmirror
neurons[ responding to another_s pain may have
been identified in human anterior cingulate
cortex (22). A large human literature documents
the effects on pain report of observation of pain
in others (23); the present data suggest that
these effects may be mediated precognitively.
There are clear limitations to the mechanistic
information that can be gleaned from human
Fig. 3. (A and B ) Bidirectional modulation of pain behavior produced by
observation of a cagemate in the formalin test. Mice, all nonsibling
cagemates (n 0 22 to 24 per group; housed together for 921 days), were
tested in dyads. In the ‘‘Same’’ condition, both mice received either 1%
formalin or 5% formalin. In the ‘‘Different’’ condition one mouse received
1% formalin and the other received 5% formalin. All groups displayed the
expected biphasic pattern of responding (A and B). A two-way (injected
dose ! observed dose) repeated measures analysis of variance (ANOVA)
revealed a significant three-way interaction (P G 0.05). (A) Data from all mice
receiving 1% formalin; the legend describes the status of the other mouse in
the dyad. (B) Data from all mice receiving 5% formalin; the legend describes
the status of the other mouse in the dyad. In (A) and (B) (note different
ordinate scales), symbols represent the mean T SEM percentage of sampled
intervals showing formalin-induced recuperative behavior (% Samples
Licking) per 5-min time bin. (C) Totals in all conditions from 0 to 40 min
after injection, after which there was no longer significantly different licking
behavior between 1% and 5% groups. ANOVA revealed a highly significant
injected dose ! observed dose interaction (F
1,88
0 9.3, P G 0.005). *P G 0.05
compared to analogous 1% condition. †P G 0.05 compared to analogous
‘‘Same’’ condition.
Fig. 4. (A to D) Thermal hyperalges ia produced by injection of acetic acid, by mere observation
of a cagemate injected with acetic acid, or both. Mice (all n onsibling cagem ates; n 0 28 to 31
per group ; housed together for 921 days) were tested in dyad s as described in Fig. 1. Before
injection, all mice were tested for baseline thermal sensitivity. In th e BW (‘‘both writhing ’’) group,
both mice were removed at time 0 0, given an injecti on of 0.9% acetic acid, and returned to their
cylinder. In the N W (‘‘none writhing’’) group, both mice were removed and replaced, with neither
receiving any injectio n. In the OW (‘‘one writhing’’) group, one mouse received an acetic a cid
injection (OW-Inj.) and the other (OW-Uninj.) did not. All mice were retested for thermal
sensitivity at 5-min intervals fo r 30 min. Symbols in (A) represent the mean T SEM paw-
withdrawal latencies (average of both hindpaws). Bars in (B) represent the mean T SEM average
change in paw-withdrawal laten cies from the baseline latency. *P G 0.05 compared to NW group
and ze ro; †P G 0.05 compared to the group immediately to the left. Bars in (C) represent the
mean T SEM percentage of sampled intervals showing writhing behavior (% Samples Writhing) of
mice receiving acetic acid (both mice in BW group; OW-Inj. mice). *P G 0.05 compared to OW-Inj.
group. (D) A significant correlation (r 0 j0. 40; P G 0.05) between the writhing behavior of one
mouse in a dyad (ordinate; BW and OW-Inj. only) and the average (postinjection) paw-withdrawal
latency of its dyadic counterpart (abscissa; BW and OW-Uninj . only).
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studies; the availability of an animal model of
empathy will allow the application of far more
powerful experimental techniques.
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Supporting Online Material
www.sciencemag.org/cgi/content/full/312/5782/1967/DC1
Materials and Methods
SOM Text
Figs. S1 to S10
References
4 April 2006; accepted 26 May 2006
10.1126/science.1128322
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