RESUMEN
ABSTRACT: Patients with chronic pain often experience exaggerated pain response and aversive emotion, such as anxiety and depression. Central plasticity in the anterior cingulate cortex (ACC) is assumed to be a critical interface for pain perception and emotion, which has been reported to involve activation of NMDA receptors. Numerous studies have documented the key significance of cGMP-dependent protein kinase I (PKG-I) as a crucial downstream target for the NMDA receptor-NO-cGMP signaling cascade in regulating neuronal plasticity and pain hypersensitivity in specific regions of pain pathway, ie, dorsal root ganglion or spinal dorsal horn. Despite this, whether and how PKG-I in the ACC contributes to cingulate plasticity and comorbidity of chronic pain and aversive emotion has remained elusive. Here, we uncovered a crucial role of cingulate PKG-I in chronic pain and comorbid anxiety and depression. Chronic pain caused by tissue inflammation or nerve injury led to upregulation of PKG-I expression at both mRNA and protein levels in the ACC. Knockdown of ACC-PKG-I relieved pain hypersensitivity as well as pain-associated anxiety and depression. Further mechanistic analysis revealed that PKG-I might act to phosphorylate TRPC3 and TRPC6, leading to enhancement of calcium influx and neuronal hyperexcitability as well as synaptic potentiation, which results in the exaggerated pain response and comorbid anxiety and depression. We believe this study sheds new light on the functional capability of ACC-PKG-I in modulating chronic pain as well as pain-associated anxiety and depression. Hence, cingulate PKG-I may represent a new therapeutic target against chronic pain and pain-related anxiety and depression.
RESUMEN
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.