Role of Opioid System in Empathy-like Behaviours in Rats

Document Type : Original Article


1 Department of Neuroscience and Basic Sciences, School of Medicine, AJA University of Medical Sciences, Tehran, Iran

2 Department of Neuroscience AND Neuroscience Research Center, Neuropharmacology Institute, Kerman University of Medical Sciences, Kerman, Iran


Background: Empathy is defined as the ability to simulate the mental states of others. Recent studies have
demonstrated empathy-like behaviors in other animals including rats and mice. The objective of the current
study was to evaluate the effect of acute administration of morphine and naloxone on cognition and
nociception changes following observing conspecifics undergoing nociceptive stimulus.
Methods: Adult male Wistar rats were used (n = 8 for each group). One cagemate received formalin injection
into the hindpaw five times within a nine-day period and the other cagemate observed the pain while being
pretreated with saline, morphine, or naloxone [10 mg/kg, intraperitoneal (i.p.)]. Pain behaviors, anxiety-like
behaviour, locomotion, balance and muscle strength were evaluated in the observer animals.
Findings: Observing a cagemate in pain increased anxiety-like behavior and reduced thermal pain threshold in the
observer animals. Administration of morphine reversed these effects and naloxone did not affect the responses.
Conclusion: Results of the current study reveal an important role for opioid receptors (ORs) in empathy for
pain, so that activation of this system dampens the empathy-like responses.


Atsak P, Orre M, Bakker P, Cerliani L, Roozendaal
B, Gazzola V, et al. Experience modulates vicarious
freezing in rats: A model for empathy. PLoS One
2011; 6(7): e21855.
Morphine Modulates Empathy for Pain Nazeri et al.
Addict Health, Autumn 2019; Vol 11, No 4 221, 07 October
2. Ben-Ami B, I, Decety J, Mason P. Empathy and prosocial behavior in rats. Science 2011; 334(6061):
3. Chen J. Empathy for distress in humans and rodents.
Neurosci Bull 2018; 34(1): 216-36.
4. Li CL, Yu Y, He T, Wang RR, Geng KW, Du R, et
al. Validating rat model of empathy for pain: effects
of pain expressions in social partners. Front Behav
Neurosci 2018; 12: 242.
5. Smith ML, Hostetler CM, Heinricher MM, Ryabinin
AE. Social transfer of pain in mice. Sci Adv 2016;
2(10): e1600855.
6. Zaniboni CR, Pelarin V, Baptista-de-Souza D,
Canto-de-Souza A. Empathy for pain: insula
inactivation and systemic treatment with midazolam
reverses the hyperalgesia induced by cohabitation
with a pair in chronic pain condition. Front Behav
Neurosci 2018; 12: 278.
7. Singer T, Seymour B, O'Doherty J, Kaube H, Dolan
RJ, Frith CD. Empathy for pain involves the
affective but not sensory components of pain.
Science 2004; 303(5661): 1157-62.
8. Langford DJ, Crager SE, Shehzad Z, Smith SB,
Sotocinal SG, Levenstadt JS, et al. Social modulation
of pain as evidence for empathy in mice. Science
2006; 312(5782): 1967-70.
9. Baptista-de-Souza D, Nunciato AC, Pereira BC,
Fachinni G, Zaniboni CR, Canto-de-Souza A. Mice
undergoing neuropathic pain induce anxiogenic-like
effects and hypernociception in cagemates. Behav
Pharmacol 2015; 26(7 Spec No): 664-72.
10. Nazeri M, Chamani G, Abareghi F, Mohammadi F,
Talebizadeh MH, Zarei MR, Shabani M. Sensory
and affective dimensions of pain and anxiety like
behaviors are altered in an animal model of pain
empathy. Iran J Psychiatry 2019; 14(3): 221-6.
11. Rutgen M, Seidel EM, Silani G, Riecansky I,
Hummer A, Windischberger C, et al. Placebo
analgesia and its opioidergic regulation suggest that
empathy for pain is grounded in self pain. Proc Natl
Acad Sci USA 2015; 112(41): E5638-E5646.
12. Nazeri M, Zarei MR, Pourzare AR, Ghahreh-Chahi
HR, Abareghi F, Shabani M. Evidence of altered
trigeminal nociception in an animal model of
fibromyalgia. Pain Med 2018; 19(2): 328-35.
13. Nazeri M, Razavinasab M, Abareghi F, Shabani M.
Role of nitric oxide in altered nociception and
memory following chronic stress. Physiol Behav
2014; 129: 214-20.
14. Maurissen JP, Marable BR, Andrus AK, Stebbins
KE. Factors affecting grip strength testing.
Neurotoxicol Teratol 2003; 25(5): 543-53.
15. Azhdari-Zarmehri H, Mohammad-Zadeh M,
Feridoni M, Nazeri M. Termination of nociceptive
behaviour at the end of phase 2 of formalin test is
attributable to endogenous inhibitory mechanisms,
but not by opioid receptors activation. Basic Clin
Neurosci 2014; 5(1): 48-54.
16. Nazeri M, Shabani M, Parsania S, Golchin L,
Razavinasab M, Abareghi F, et al. Simultaneous
impairment of passive avoidance learning and
nociception in rats following chronic swim stress.
Adv Biomed Res 2016; 5: 93.
17. Mogil JS. The surprising empathic abilities of
rodents. Trends Cogn Sci 2012; 16(3): 143-4.
18. Zubieta JK, Bueller JA, Jackson LR, Scott DJ, Xu Y,
Koeppe RA, et al. Placebo effects mediated by
endogenous opioid activity on mu-opioid receptors. J
Neurosci 2005; 25(34): 7754-62.
19. Li Z, Lu YF, Li CL, Wang Y, Sun W, He T, et al.
Social interaction with a cagemate in pain facilitates
subsequent spinal nociception via activation of the
medial prefrontal cortex in rats. Pain 2014; 155(7):
20. Konig M, Zimmer AM, Steiner H, Holmes PV,
Crawley JN, Brownstein MJ, et al. Pain responses,
anxiety and aggression in mice deficient in
pre-proenkephalin. Nature 1996; 383(6600): 535-8.