Development of chronic pain involves alterations in peripheral nociceptors as well as elevated neuronal activity in multiple regions of the CNS. Previous pharmacological and behavioral studies suggest that peripheral acid-sensing ion channels (ASICs) contribute to pain sensation, and the expression of ASIC subunits is elevated in the rat spinal dorsal horn (SDH) in an inflammatory pain model. However, the cellular distribution and the functional consequence of increased ASIC subunit expression in the SDH remain unclear. Here, we identify the Ca²⁺-permeable, homomeric ASIC1a channels as the predominant ASICs in rat SDH neurons and downregulation of ASIC1a by local rat spinal infusion with specific inhibitors or antisense oligonucleotides markedly attenuated complete Freund's adjuvant (CFA)-induced thermal and mechanical hypersensitivity. Moreover,in vivoelectrophysiological recording showed that the elevated ASIC1a activity is required for two forms of central sensitization: C-fiber-induced “wind-up” and CFA-induced hypersensitivity of SDH nociceptive neurons. Together, our results reveal that increased ASIC activity in SDH neurons promotes pain by central sensitization. Specific blockade of Ca²⁺-permeable ASIC1a channels thus may have antinociceptive effect by reducing or preventing the development of central sensitization induced by inflammation.

Empathy for the pain experience of others can lead to the activation of pain-related brain areas and can even induce aberrant responses to pain in human observers. Recent evidence shows this high-level emotional and cognitive process also exists in lower animals; however, the mechanisms underlying this phenomenon remain unknown. In the present study we found that, after social interaction with a rat that had received subcutaneous injection of bee venom (BV), only the cagemate observer (CO) but not the noncagemate observer (NCO) showed bilateral mechanical hypersensitivity and an enhanced paw flinch reflex following BV injection. Moreover, neuronal activities labeled by c-Fos immunoreactivity in the spinal dorsal horn of CO rats were also significantly increased relative to the control 1 hour after BV injection. A stress-related response can be excluded because serum corticosterone concentration following social interaction with demonstrator rats in pain was not changed in CO rats relative to NCO and isolated control rats. Anxiety can also be excluded because anxiety-like behaviors could be seen in both the CO and NCO rats tested in the open-field test. Finally, bilateral lesions of the medial prefrontal cortex eliminated the enhancement of the BV-induced paw flinch reflex in CO rats, but bilateral lesions of either the amygdala or the entorhinal cortex failed. Together, we have provided another line of evidence for the existence of familiarity-dependent empathy for pain in rats and have demonstrated that the medial prefrontal cortex plays a critical role in processing the empathy-related enhancement of spinal nociception.