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Papers of the Week


Papers: 8 Aug 2020 - 14 Aug 2020


Animal Studies


2020 Aug 05


Pain

Nociceptor-localized cGMP-dependent protein kinase I is a critical generator for central sensitization and neuropathic pain.

Authors

Wang F, Ma S-B, Tian Z-C, Cui Y-T, Cong X-Y, Wu W-B, Wang F-D, Li Z-Z, Han W-J, Wang T-Z, Sun Z-C, Zhang F-L, Xie R-G, Wu S-X, Luo C
Pain. 2020 Aug 05.
PMID: 32773598.

Abstract

Patients with neuropathic pain often experience exaggerated pain and anxiety. Central sensitization has been linked with the maintenance of neuropathic pain and may become an autonomous pain generator. Conversely, emerging evidence accumulated that central sensitization is initiated and maintained by ongoing nociceptive primary afferent inputs. However, it remains elusive what mechanisms underlie this phenomenon and which peripheral candidate contributes to central sensitization that accounts for pain hypersensitivity and pain-related anxiety. Previous studies have implicated peripherally-localized cGMP-dependent protein kinase I (PKG-I) in plasticity of nociceptors and spinal synaptic transmission as well as inflammatory hyperalgesia. However, whether peripheral PKG-I contributes to cortical plasticity and hence maintains nerve injury-induced pain hypersensitivity and anxiety is unknown. Here we demonstrated significant upregulation of PKG-I in ipsilateral L3 DRG, no change in L4 DRG and downregulation in L5 DRG upon spared nerve injury (SNI). Genetic ablation of PKG-I specifically in nociceptors or posttreatment with intervertebral foramen injection of PKG-I antagonist, KT5823 attenuated the development and maintenance of SNI-induced bilateral pain hypersensitivity and anxiety. Mechanistic analysis revealed that activation of PKG-I in nociceptors is responsible for synaptic potentiation in ACC upon peripheral neuropathy via presynaptic mechanisms involving BDNF signaling. Our results revealed that PKG-I expressed in nociceptors is a key determinant for cingulate synaptic plasticity after nerve injury, which contributes to the maintenance of pain hypersensitivity and anxiety. Thereby, this study presents a strong basis for opening up a novel therapeutic target, PKG-I in nociceptors for treatment of comorbidity of neuropathic pain and anxiety with least side effects.