Functional peripheral and central vagal neural circuits of interoception inhibiting pain Interoception is the sense of the physiological condition of the body, and is critical for maintaining homeostasis and regulating cognitive and emotional processes. The neural processing of interoception can be regulated by electrical stimulation of the vagus nerve, which led to an FDA-approved therapy for seizure and depression. Interestingly, vagal stimulation also modulates intractable chronic pain in patients. However, the road to improving chronic pain management through the regulation of interoceptive inputs is blocked by our ignorance of the neurobiological mechanisms whereby vagal activity modulates chronic pain, posing a significant hurdle. To overcome this hurdle, we will focus on the neural mechanisms of vagal modulation in a mouse model of inflammation in temporomandibular joint (TMJ), a surrogate model of temporomandibular disorders (TMD). TMD is a prevalent form of chronic pain that often occurs as a comorbidity with other chronic pain conditions, such as migraine and fibromyalgia. Since chronic pain involves a wide range of neural processes ranging from peripheral nociception to affective and cognitive processing in the brain, it is possible that interoceptive inputs regulate pain pathways through multiple peripheral and central mechanisms. Vagal stimulation was suggested to inhibit transmission of pain signals at spinal cord through the regulation of descending pain modulatory pathways. Considering the high comorbidity of chronic pain and affective disorders, such as anxiety or depression, vagal inputs likely modulate pain through regulation of brain regions involved in emotional regulation. Furthermore, pain is driven by nociceptive processing by pain-sensing nerves at peripheral tissues, but vagal regulation of nociception in the periphery has not been reported. Here, our objective is to determine functional neural mechanisms by which interoception inhibits pain. Our central hypothesis is that vagal interoceptive circuits intersect with peripheral and central nociceptive pathways to inhibit pain from TMJ. We will test this hypothesis in the following specific aims.

Interoception is the sense of the physiological condition of the body and critical for maintaining homeostasis and regulating cognitive and emotional processes. Interestingly, vagal stimulation (major interoception input) modulates intractable chronic pain in patients. Lack of understanding about neurobiological mechanisms whereby vagal activity modulates chronic pain poses a significant hurdle for improving chronic pain management through the regulation of interoceptive inputs. Here, we focus on studying neural mechanisms of vagal modulation in a mouse model of temporomandibular disorders (TMD). TMD are the most prevalent orofacial pain conditions that involve the temporomandibular joint (TMJ), chewing muscles, and associated head and neck musculoskeletal structures and patients with TMD suffer from myofascial pain, limited mandibular motion, and TMJ sounds and the prevalence among U.S. adults is about 25% who experiencing TMD at least once in their lifetime and among them over 35 million suffer from TMD pain and resulting severe psychosocial and economic burden is more than $60 billion per year. Here, we will study functional neural mechanisms of interoception inhibiting pain. Our central hypothesis is that vagal interoceptive circuits intersect with peripheral and central nociceptive pathways to inhibit pain from TMJ.