Abstract
Empathy for pain (vicariously felt pain), an ability to feel, recognize, understand and share the painful emotions of others, has been gradually accepted to be a common identity in both humans and rodents, however, the underlying neural and molecular mechanisms are largely unknown. Recently, we have developed a rat model of empathy for pain in which pain can be transferred from a cagemate demonstrator (CD) in pain to a naïve cagemate observer (CO) after 30 min dyadic priming social interaction. The naïve CO rats display both mechanical pain hypersensitivity (hyperalgesia) and enhanced spinal nociception. Chemical lesions of bilateral medial prefrontal cortex (mPFC) abolish the empathic pain response completely, suggesting existence of a top-down facilitation system in production of empathy for pain. However, the social transfer of pain was not observed in non-cagemate observer (NCO) after dyadic social interaction with a non-cagemate demonstrator (NCD) in pain. Here we showed that dyadic social interaction with a painful CD resulted in elevation of circulating norepinephrine (NE) and increased neuronal activity in the locus coeruleus (LC) in the CO rats. Meanwhile, CO rats also had over-expression of P2X3, but not TRPV1, in the dorsal root ganglia (DRG). Chemical lesion of the LC-NE neurons by systemic DSP-4 and pharmacological inhibition of central synaptic release of NE by clonidine completely abolished increase in circulating NE and P2X3 receptor expression, as well as the sympathetically-maintained development of empathic mechanical hyperalgesia. However, in the NCO rats, neither the LC-NE neuronal activity nor the P2X3 receptor expression was altered after dyadic social interaction with a painful NCD although the circulating corticosterone and NE were elevated. Finally, in the periphery, both P2X3 receptor and α1 adrenergic receptor were found to be involved in the development of empathic mechanical hyperalgesia. Taken together with our previous results, empathy for pain observed in the CO rats is likely to be mediated by activation of the top-down mPFC-LC/NE-sympathoadrenomedullary (SAM) system that further up-regulates P2X3 receptors in the periphery, however, social stress observed in the NCO rats is mediated by activation of both hypothalamic-pituitary-adrenocortical axis and SAM axis.
Highlights
Pain can be perceived directly by self experience and vicariously through social interaction and communication (Langford and de C Williams, 2014; Martin et al, 2014; Mogil, 2015; Williams and Craig, 2016; Chen, 2017)
The results showed that pre-antagonism against P2X3 receptors with A317491 (0.2 mg/10 μl) prevented the empathic mechanical hyperalgesia from occurring in the injected limb of the cagemate observer (CO) rats (Post-treatment vs. Pre-treatment, P > 0.05, n = 16; Figure 3D), while the empathic mechanical hyperalgesia remained unchanged in the non-injected hindlimb
Selective Up-Regulation of Primary P2X3 Nociceptor by LC/NE-SAM Axis Activation Serves as Molecular Basis for Development of Empathic Mechanical Hyperalgesia. We provided another line of new evidence showing that the elevated circulating NE driven by the LC/NE-SAM system selectively up-regulates the expression of P2X3 receptors, but not thermal nociceptor TRPV1, in the DRG that serves as peripheral molecular basis for development of the empathic mechanical hyperalgesia identified in the CO rats
Summary
Pain can be perceived directly by self experience and vicariously through social interaction and communication (Langford and de C Williams, 2014; Martin et al, 2014; Mogil, 2015; Williams and Craig, 2016; Chen, 2017). The empathic mechanical pain hypersensitivity (or hyperalgesia) identified in naïve observer rats has been further demonstrated to be mediated by top-down facilitation from medial prefrontal cortex (mPFC) to the spinal dorsal horn (Li et al, 2014). It is interesting to note that neural responses of primary olfactory neurons to threat-predictive odor stimuli could be enhanced by fear learning (Kass et al, 2013), inspiring our hypothetical account of top-down regulation of primary nociceptors by empathic responses from the brain
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
