Highly synchronized cortical circuit dynamics mediate spontaneous pain in mice

Abstract

Cortical neural dynamics mediate information processing for the cerebral cortex, implicated in fundamental biological processes, such as vision and olfaction, in addition to neurological and psychiatric diseases. Spontaneous pain is a key feature of human neuropathic pain. Whether spontaneous pain pushes cortical network into an aberrant state, and if so, whether it can be brought back to a 'normal' operating range to ameliorate pain are unknown. Using a clinically relevant mouse model of neuropathic pain with spontaneous pain-like behavior, we report that orofacial spontaneous pain activated a specific area within the primary somatosensory cortex (S1), displaying synchronized neural dynamics revealed by intravital two-photon calcium imaging.This synchronization was underpinned by local GABAergic interneuron hypoactivity. Paininduced cortical synchronization could be attenuated by manipulating local S1 networks or clinically effective pain therapies. Specifically, both chemogenetic inhibition of pain-related c-Fosexpressing neurons, and selective activation of GABAergic interneurons, significantly attenuated S1 synchronization. Clinically effective pain therapies including carbamazepine and nerve root decompression could also dampen S1 synchronization. More importantly, restoring a 'normal' range of neural dynamics, through attenuating pain-induced S1 synchronization, alleviated painlike behavior. These results suggest spontaneous pain pushes S1 regional network into a synchronized state, whereas reversal of this synchronization alleviates pain.

Discovering chronic pain treatments: better animal models might help us get there

“…In this issue of the JCI , Ding, Fischer, and co-authors ( 19 ) describe a different trigeminal neuropathic pain model that exhibits several key features that have been on investigators’ wish lists for years, including (a) face validity: the foramen lacerum impingement of trigeminal nerve root (FLIT) model exhibits robust spontaneous pain behaviors (facial grimacing, excessive facial grooming, intermittent eye squinting) and clinically relevant functional consequences of persistent pain (body weight loss, decreased wood chewing, soft food preference, increased incisor length, increased anxiety behaviors, and sexual dysfunction), which are consistent with the clinical signs and symptoms of human trigeminal neuralgia (TN); (b) construct validity: the FLIT model utilizes a clever, reversible trigeminal nerve root compression that mimics the human pathology of trigeminal nerve root impingement at its entry zone ( 20 ); and (c) predictive validity, which includes nearly complete ineffectiveness of NSAIDS, partial effectiveness of carbamazepine, and robust effectiveness of trigeminal nerve root decompression surgery, a definitive treatment for patients with TN with vascular compression ( 21 ).…”

“…Even more important, Ding, Fischer, and colleagues ( 19 ) then used the model to make important observations regarding cortical dynamics that underlie the mechanism of TN pain ( Figure 1 ). Most studies of central sensitization focus on changes in the periphery at the level of the nociceptor and its synaptic connection at the dorsal horn of the spinal cord.…”

“…The authors further demonstrated that this unrestrained activity was due to hypoactive GABAergic interneuron activity. Important control experiments showed that manipulations of an adjacent somatosensory cortex region and masseter muscle atrophy were not mechanistically linked to TN-like pain behaviors ( 19 ).…”

“…But the study by Ding, Fischer, and co-authors ( 19 ) also brings up questions for further investigation. One of the most intriguing questions in pain research relates to the point at which acute, temporary sensitization of the nociceptive system becomes persistent and the mechanism driving this persistence.…”

“…Thus, one can question whether the phenotype produced by the FLIT procedure meets the criteria for chronic pain, since the current definition considers the key role of neuroplasticity in pain maintenance. While the authors have not addressed this point in their study, the proposed model and methodology provide an excellent tool to systematically investigate the interaction between the peripheral and central nervous systems that leads to the establishment of chronic pain and the critical time point at which chronic pain occurs ( 19 ).…”