Suppression Of Glutamatergic Neurons In The Lateral Habenula Alleviates Neuropathic Allodynia

Objective:The mechanism of neuropathic pain remains not fully understood and effective treatments are still lacking.Lateral habenula(LHb)is considered as an ’anti-reward’ nucleus.Pain chronification is accompanied with reward deficiency.However,the role of LHb in neuropathic pain is unclear.This study aimed to reveal the role of LHb glutamatergic neurons in neuropathic pain by using the method of optogenetics.Methods and results:[1]Compared with the sham group,LHb glutamatergic neurons in neuropathic mice receiving partial sciatic ligation(PSL)and partial infraorbital nerve transection(p-IONX)showed increased spontaneous firing frequency and burst firing rate.More neurons were activated by peripheral noxious mechanical stimulation in PSL group compared with the sham group.[2]Selective inhibition of LHb glutamatergic neurons expressing photosensitive protein Arch by yellow laser increased the pain threshold of mice to mechanical stimulation in bilateral hind paws in both PSL and p-IONX groups,but not in the sham group.In the conditioned place preference assay,mice in both sham and PSL groups showed preference for the yellow light paired chamber.[3]Selective activation of LHb glutamatergic neurons expressing photosensitive protein ChR2 by blue laser had no effect on mechanical pain thresholds.In the conditioned place preference experiment,mice in the sham group showed aversion for the blue light paired chamber,but those in the PSL group did not.[4]Chemogenetic inhibition of LHb glutamatergic neurons expressing hM4D by CNO(1 mg/kg)increased the thermal pain thresholds of the left vibrissal pad and mechanical pain thresholds of the left hind paw.[5]LHb DBS at 1 Hz applied for 7 days after PSL surgery increased the mechanical pain thresholds in the left hind paw.Conclusion:Under physiological condition,glutamatergic neurons in the LHb respond to input of sensory information and participate in encoding aversion component of pain.Under neuropathic condition,the activity of these neurons increased.Suppression of their activity alleviates somatic and orofacial pain-associated widespread neuropathic allodynia,indicating a causal link between the activity of LHb glutamatergic neurons and neuropathic pain.Our results suggest that LHb can be a potential treatment target for neuropathic allodynia.