BackgroundPost-traumatic stress disorder (PTSD) is a serious stress-related disorder caused by traumatic experiences. However, identifying a key therapy that can be used for PTSD treatment remains difficult. Ketamine, a well-known dissociative anesthetic, is considered safe to be used in anesthesia, pain management, and antidepressant actions since 1970. At present, it is still controversial whether PTSD can be treated with ketamine. The authors performed a meta-analysis to determine whether the use of perioperative ketamine lowers the incidence of PTSD.MethodsCochrane Central Register of Controlled Trials, Embase, PubMed, and Web of Science were searched to examine the use of ketamine for the treatment of PTSD among soldiers with combating experience. Studies were included if they were randomized placebo-controlled, case-control, and cohort studies. The primary outcome was the incidence of PTSD in the later stage of the wounded or burn soldiers. The secondary outcome was the influence of ketamine on PTSD-scale scores for early and chronic PTSD, respectively.ResultsOur search yielded a total of three studies (n = 503 patients) comparing the use of ketamine (n = 349) to control (n = 154). The available evidence showed no significant difference in the incidence of PTSD between combatant soldiers on the battlefield with or without ketamine treatment (risk ratio = 0.81, 95% CI, 0.63–1.04; P = 0.10). In 65 patients from three trials, ketamine was not only ineffective in treating early PTSD but also lead to exacerbation of the disease (risk ratio = 2.45, 95% CI, 1.33–3.58; P < 0.001). However, in 91 patients from the other three trials, ketamine is effective in treating chronic PTSD (risk ratio = −3.66, 95% CI, −7.05 to −0.27; P = 0.03).ConclusionKetamine was not effective on lower the PTSD incidence for soldiers on the battlefield, nor on the PTSD-scale scores in early PTSD patients. However, it may improve the PTSD-scale scores for chronic conditions.Systematic Review Registrationhttps://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021255516, PROSPERO, identifier: CRD42021255516.

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.

Laboratory rodents are gregarious in nature and have a feeling of empathy when witnessing a familiar conspecific in pain. The rodent observers express two levels of empathic responses: observational contagious pain (OCP) and consolation. Here we examined the sex and species difference of OCP and consolation in male and female mice and rats. We observed no species difference in both OCP and consolation, but significant species difference in general social (allo-mouth and/or allo-tail sniffing) and non-social (self-grooming) behaviors. For sex difference, male mouse observers showed more allolicking and allogrooming behaviors toward a familiar conspecific in pain during and longer time increase in pain sensitivity after the PDSI than female mouse observers. However, no sex difference was observed in rats. Our results highlighted an evolutionary view of empathy that social animals including rodents also have the ability to feel, recognize, understand and share the other's distressing states.

Empathy for pain is referred to as an evolutionary behavior of social animals and humans associated with the ability to feel, recognize, understand and share the other's distressing (pain, social rejection and catastrophe) states. Impairment of empathy can definitely lead to deficits in social communication and sociability (attachment, bond, reciprocity, altruism and morality) that may be fundamental to some psychiatric disorders such as autism spectrum disorder (ASD), psychopathy, misconduct, antisocial personality disorder and schizophrenia. So far, the underlying mechanisms of empathy are poorly known due to lack of animal models and scarce understanding of its biological basis. Recently, we have successfully identified and validated the behavioral identities of empathy for pain in rats that can be widely used as a rodent model for studying the underlying biological mechanisms of empathy. Priming dyadic social interaction between a naive cagemate observer (CO) and a cagemate demonstrator (CD), rather than a non-cagemate, in pain for 30 min in a testing box can repeatedly and constantly result in empathic responses of the CO toward the familiar CD's distressing condition, displaying as allo-licking at the injury site, allo-grooming at the body and social transfer of pain. The familiarity-based, distress-specific social consolation and subsequent social transfer of pain can be qualitatively and quantitatively rated as experimental biomarkers for empathy for pain. The rodent model of empathy for pain is state-of-the-art and has more advantages than the existing ones used for social neuroscience since it can reflect sensory, emotional and cognitive processes of the brain in running the prosocial and altruistic behaviors in animals who could not report verbally. Here we would like to provide and share the protocol of the model for wide use.

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