Secondary somatosensory cortex glutamatergic innervation of the thalamus facilitates pain

Abstract

Although the secondary somatosensory cortex (SII) is known to be involved in pain perception, its role in pain modulation and neuropathic pain is yet unknown. In this study, we found that glutamatergic neurons in deep layers of the SII (SIIGlu) responded to bilateral sensory inputs by changing their firing with most being inhibited by contralateral noxious stimulation. Optical inhibition and activation of unilateral SIIGlu reduced and enhanced bilateral nociceptive sensitivity, respectively, without affecting mood status. Tracing experiments revealed that SIIGlu sent dense monosynaptic projections to the posterolateral nucleus (VPL) and the posterior nucleus (Po) of the thalamus. Optical inhibition and activation of projection terminals of SIIGlu in the unilateral VPL and Po inhibited and facilitated pain on the contralateral side, respectively. After partial sciatic nerve ligation, SIIGlu became hyperactive as evidenced by higher frequency of spontaneous firing, but the response patterns to peripheral stimulation remained. Optical inhibition of SIIGlu alleviated not only bilateral mechanical allodynia and thermal hyperalgesia but also the negative affect associated with spontaneous pain. Inhibition of SIIGlu terminals in the VPL and Po also relieved neuropathic pain. This study revealed that SIIGlu and the circuits to the VPL and Po constitute a part of the endogenous pain modulatory network. These corticothalamic circuits became hyperactive after peripheral nerve injury, hence contributes to neuropathic pain. These results justify proper inhibition of SIIGlu and associated neural circuits as a potential clinical strategy for neuropathic pain treatment.