Neuropathic pain affects 7-10% of the global population, and one of its characteristics is sensitization of somatosensory nervous system. Altered expression of ion channels and receptors has been found to be involved in neuronal hyperexcitability after injury to somatosensory nervous system, it is, however, unknown that if ion channels and receptors could gain qualitative changes on the level of structure organization when they are excessively expressed in same one neuron during the development of neuropathic pain. Here we show first that not only the expression of voltage-gated sodium channels Nav1.7 (SCN9A), Nav1.8 (SCN10A) and TRKB (also named NTRK2) increased in DRG neurons of patients with over 3-month severe neuropathic pain induced by brachial plexus avulsion (BPA), but also Nav1.7 and Nav1.8 formed supramolecular active clusters with or without TRKB in DRG neurons of mice with chronic neuropathic pain induced by spared nerve injury or diabetic neuropathy and of BPA pain patients with neuropathic pain. Nav1.7, Nav1.8 and TRKB might function in a coordinated manner in orderly organized supramolecular active clusters to geometrically increase the hyperexcitability of pathological DRG neurons. Our findings suggest that supramolecular active clusters of Nav1.7, Nav1.8 and TRKB might need be targeted for curing neuropathic pain, and that inhibition of both Nav1.7 and Nav1.8 might be required to achieve efficient relief of neuropathic pain.

The authors have declared no competing interest.

Changgeng Peng is supported by the National Natural Science Foundation of China (32070977, 51971236, 31871063), and National Major Science and Technology Projects of China (2018ZX09733001-006-005). Liting Sun is supported by the National Natural Science Foundation of China (82101320). Rougang Xie is supported by the National Natural Science Foundation of China (82171212, 81870867) and Ministry of Science and Technology of China (2021ZD0203205). Hongyan Shuai is supported by the National Natural Science Foundation of China (82060149).

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The avulsed roots of the affected brachial plexus and the dislocated cervical DRG tissues were resected during the surgical process of nerve reconstruction or transplantation under the ethic permit (KY20222228) approved by the Ethics Committee of Xijing Hospital, the first affiliated hospital of Fourth Military Medical University. Normal cervical DRG tissues from naturally aborted 29-weeks human embryos were collected according to the ethic permit (MECDU-201909-1) approved by Dali University.

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