The prelimbic cortex (PL) is actively engaged in pain modulation. The infralimbic cortex (IL) has been reported to regulate the PL. However, how this regulation affects pain remains unclear. In the present study, we recorded temporary hyper-activity of PL pyramidal neurons responding to nociceptive stimuli, but a temporary hypo-function of the IL by in vivo electrophysiological recording in rats with peripheral inflammation. Manipulation of the PL or IL had opposite effects on thermal hyperalgesia. Furthermore, the functional connectivity and chemogenetic regulation between the subregions indicated an inhibitory influence of the IL on the PL. Activation of the pathway from the IL to the PL alleviated thermal hyperalgesia, whereas its inhibition exacerbated chronic pain. Overall, our results suggest a new mechanism underlying the role of the medial prefrontal cortex in chronic pain: hypo-function of the IL leads to hyperactivity of the PL, which regulates thermal hyperalgesia, and thus contributes to the chronicity of pain.

The absence of a comprehensive understanding of the neural basis of spontaneous pain limits the development of therapeutic strategies targeting this primary complaint of patients with chronic pain. Here we report a distinct neuronal ensemble within the prelimbic cortex which processes signals related to spontaneous pain in rats with chronic inflammatory pain. This neuronal ensemble specifically encodes spontaneous pain-related behaviors, independently of other locomotive and evoked behaviors. Activation of this neuronal ensemble elicits marked spontaneous pain-like behaviors and enhances nociceptive responses, whereas prolonged silencing of its activities alleviates spontaneous pain and promotes overall recovery from inflammatory pain. Notably, afferents from the primary somatosensory cortex and infralimbic cortex bidirectionally modulate the activities of the spontaneous pain-responsive prelimbic cortex neuronal ensemble and pain behaviors. These findings reveal the cortical basis of spontaneous pain at the neuronal level, highlighting a distinct neuronal ensemble within the prelimbic cortex and its associated pain-regulatory brain networks.

Spontaneous pain occurring without apparent external stimuli, is a significant complaint of individuals with chronic pain whose mechanisms, somewhat surprisingly, remain poorly understood. Over the past decades, neuroimaging studies start to reveal brain activities accompanying spontaneous pain. Meanwhile, a variety of animal models and behavioral tests have been established, including non-reflexive tests and free-choice tests, which have been shown to be effective in assessing spontaneous pain. For the spontaneous pain mechanisms, multiple lines of research mainly focus on three aspects: (1) sensitization of peripheral nociceptor receptors and ion channels, (2) spontaneous neuronal firing and abnormal activity patterns at the dorsal root ganglion and spinal cord level, (3) functional and structural alterations in the brain, particularly the limbic system and the medial pain pathway. Despite accumulating evidence revealing distinct neuronal mechanisms from evoked pain, we are still far from full understanding of spontaneous pain, leaving a big gap between bench and bedside for chronic pain treatment. A better understanding of the neural processes in chronic pain, with specific linkage as to which anatomical structures and molecules related to spontaneous pain perception and comorbidities, will greatly improve our ability to develop novel therapeutics.