The similar past pain experience evokes both observational contagious pain and consolation in stranger rat observers.

Laboratory rodents have been shown to have an ability to recognize the injury site and negative emotional state of their conspecifics in pain, resulting in empathic consoling behaviors and observational contagious pain (OCP). However, these empathic responses have been shown to be familiarity-dependent. In this report, we further explored whether the past pain experience could evoke empathic response in stranger observers. In our rodent model, two types of empathic response have been identified from naive cagemate observer (COnaive) during and after a priming dyadic social interaction (PDSI) with a cagemate demonstrator in pain (CDpain): the consolation and OCP. Consolation is represented by allolicking and allogrooming behaviors toward the CDpain, while the OCP is represented by a long-term mechanical pain hypersensitivity. The current results showed that: (1) neither the consolation nor OCP could be identified in the naive noncagemate observer (NCOnaive) during and after a PDSI with a noncagemate demonstrator in pain (NCDpain); (2) nor were the two types of empathic response seen in the NCO, who had just experienced acute pain (NCOpainexp), during and after a PDSI with a naive unfamiliar conspecific (NCDnaive). However, both the consolation and OCP were dramatically identified in the NCOpainexp during and after a PDSI with a NCD in pain (NCDpain). The current results demonstrated that the past pain experience can evoke both consolation and OCP in stranger rat observers when witnessing a conspecific in pain, implicating that the processing of empathy for pain can be modulated by past negative mood experience.

Validating Rat Model of Empathy for Pain: Effects of Pain Expressions in Social Partners.

Pain can be socially transferred between familiar rats due to empathic responses. To validate rat model of empathy for pain, effects of pain expressions in a cagemate demonstrator (CD) in pain on empathic pain responses in a naïve cagemate observer (CO) after 30 min priming dyadic social interactions (PDSI) were evaluated. The CD rats were prepared with four pain models: bee venom (BV), formalin, complete Freund's adjuvant (CFA), and spared nerve injury (SNI). Both BV and formalin tests are characterized by displayable and eye-identifiable spontaneous pain-related behaviors (SPRB) immediately after treatment, while CFA and SNI models are characterized by delayed occurrence of evoked pain hypersensitivity but with less eye-identifiable SPRB. After 30 min PDSI with a CD immediately after BV and formalin, respectively, the empathic mechanical pain hypersensitivity (EMPH) could be identified at both hind paws in CO rats. The BV-or formalin-induced EMPH in CO rats lasted for 4-5 h until full recovery. However, EMPH failed to develop in CO after socially interacting with a CD immediately after CFA, or 2 h after BV when SPRB completely disappeared. The CO's EMPH was partially relieved when socially interacting with an analgecized CD whose SPRB had been significantly suppressed. Moreover, repeated exposures to a CD in pain could enhance EMPH in CO. Finally, social transfer of pain hypersensitivity was also identified in CO who was being co-housed in pairs with a conspecific treated with CFA or SNI. The results suggest that development of EMPH in CO rats would be determined not only by extent of familiarity but also by visually identifiable pain expressions in the social partners during short period of PDSI. However, the visually unidentifiable pain can also be transferred to naïve cagemate when being co-housed in pairs with a distressed conspecific. In summary, the vicariously social contagion of pain between familiar rats is dependent upon not only expressions of pain in social partners but also the time that dyads spent in social communications. The rat model of empathy for pain is a highly stable, reproducible and valid model for studying the neural mechanisms of empathy in lower animals.

Ethanol Increases Mechanical Pain Sensitivity in Rats via Activation of GABAA Receptors in Medial Prefrontal Cortex.

Ethanol is widely known for its ability to cause dramatic changes in emotion, social cognition, and behavior following systemic administration in humans. Human neuroimaging studies suggest that alcohol dependence and chronic pain may share common mechanisms through amygdala-medial prefrontal cortex (mPFC) interactions. However, whether acute administration of ethanol in the mPFC can modulate pain perception is unknown. Here we showed that bilateral microinjections of ethanol into the prelimbic and infralimbic areas of the mPFC lowered the bilateral mechanical pain threshold for 48 h without influencing thermal pain sensitivity in adult rats. However, bilateral microinjections of artificial cerebrospinal fluid into the mPFC or bilateral microinjections of ethanol into the dorsolateral PFC (also termed as motor cortex area 1 in Paxinos and Watson's atlas of The Rat Brain. Elsevier Academic Press, Amsterdam, 2005) failed to do so, suggesting regional selectivity of the effects of ethanol. Moreover, bilateral microinjections of ethanol did not change the expression of either pro-apoptotic (caspase-3 and Bax) or anti-apoptotic (Bcl-2) proteins, suggesting that the dose was safe and validating the method used in the current study. To determine whether γ-aminobutyric acid A (GABAA) receptors are involved in mediating the ethanol effects, muscimol, a selective GABAA receptor agonist, or bicuculline, a selective GABAA receptor antagonist, was administered alone or co-administered with ethanol through the same route into the bilateral mPFC. The results showed that muscimol mimicked the effects of ethanol while bicuculline completely reversed the effects of ethanol and muscimol. In conclusion, ethanol increases mechanical pain sensitivity through activation of GABAA receptors in the mPFC of rats.

[Empathy for pain: A novel bio-psychosocial-behavioral laboratory animal model].

Empathy, a basic prosocial behavior, is referred to as an ability to understand and share others' emotional state. Generally, empathy is also a social-behavioral basis of altruism. In contrast, impairment of empathy development may be associated with autism, narcissism, alexithymia, personality disorder, schizophrenia and depression. Thus, study of the brain mechanisms of empathy has great importance to not only scientific and clinical advances but also social harmony. However, research on empathy has long been avoided due to the fact that it has been considered as a distinct feature of human beings from animals, leading to paucity of knowledge in the field. In 2006, a Canadian group from McGill University found that a mouse in pain could be shared by its paired cagemate, but not a paired stranger, showing decreased pain threshold and increased pain responses through emotional contagion while they were socially interacting. In 2014, we further found that a rat in pain could also be shared by its paired cagemate 30 min after social interaction, showing long-term decreased pain threshold and increased pain responses, suggesting persistence of empathy for pain (empathic memory). We also mapped out that the medial prefrontal cortex, including the anterior cingulate cortex, prelimbic cortex and infralimbic cortex, is involved in empathy for pain in rats, suggesting that a neural network may be associated with development of pain empathy in the CNS. In the present brief review, we give a brief outline of the advances and challenges in study of empathy for pain in humans and animals, and try to provide a novel bio-psychosocial-behavioral model for study of pain and its emotional comorbidity using laboratory animals.