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

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 dorsal root ganglia (DRG), no change in L4 DRG, and downregulation in L5 DRG upon spared nerve injury. Genetic ablation of PKG-I specifically in nociceptors or post-treatment with intervertebral foramen injection of PKG-I antagonist, KT5823, attenuated the development and maintenance of spared nerve injury–induced bilateral pain hypersensitivity and anxiety. Mechanistic analysis revealed that activation of PKG-I in nociceptors is responsible for synaptic potentiation in the anterior cingulate cortex upon peripheral neuropathy through presynaptic mechanisms involving brain-derived neurotropic factor 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.

Extracellular matrix protein laminin β1 regulates pain sensitivity and anxiodepression-like behaviors in mice

“…Whole-cell patch-clamp recording was performed as described previously (79). Briefly, three weeks after viral injection of AAV-shLamb1 or AAV-scrambled shRNA into unilateral ACC, mice were anesthetized with urethane (1.2 g/kg, i.p.…”

Global Research on Neuropathic Pain Rehabilitation over the Last 20 Years

“…Recent studies have shown that cGMP-dependent protein kinase I, a nociceptor locator, is a key pro-ducer of central sensitization and neuropathic pain [45]. We found that activation of microglia attenuated synaptic transmission and reduced neuroinflammation, synaptic function, and neuralgia.…”

“…The latest clinical practice guidelines also point to the use of sensors and mechanical devices can help patients achieve functional movement, enhance recovery, and increase neural plasticity, as well as potential adjuncts [ 42 – 44 ] Central sensitization: central sensitization is a kind of hypersensitivity to pain caused by central neural plasticity, which is interwoven with psychoneuroimmunological interactions [ 34 , 35 ], and is of great significance for the diagnosis and treatment of pain. Recent studies have shown that cGMP-dependent protein kinase I, a nociceptor locator, is a key producer of central sensitization and neuropathic pain [ 45 ]. We found that activation of microglia attenuated synaptic transmission and reduced neuroinflammation, synaptic function, and neuralgia.…”

Blocking the Spinal Fbxo3/CARM1/K+ Channel Epigenetic Silencing Pathway as a Strategy for Neuropathic Pain Relief

“…First, in contrast to the current study, which investigated the histone arginine methylation pattern in L4-5 spinal dorsal horn, their study focused on L4 DRG. Because a study has shown that pain-associated protein expression varies in different levels of DRG after spared nerve injury-induced neuropathic pain model [51]; and compelling evidence studies has indicated the sensory impulses of the DRG, which project onto the spinal cord, are required for neuropathic pain [52]. These evidence indicated that protein expression varies in different levels of DRG could results distinct protein changes in the center nerve system; and therefore underlies the discrepancy in CARM1 expression.…”