Cyclic GMP-dependent protein kinase-I localized in nociceptors modulates nociceptive cortical neuronal activity and pain hypersensitivity.
Chronic pain represents a frequent and poorly understood public health issue. Numerous studies have documented the key
significance of plastic changes along the somatosensory pain pathways in chronic pain states. Our recent study demonstrated
that the cGMP-dependent protein kinase I (PKG-I) specifically localized in nociceptors constitutes a key mediator of
hyperexcitability of primary sensory neurons and spinal synaptic plasticity after inflammation. However, whether PKG-I in
nociceptors further affects the cortical plasticity in the ascending pain pathways under pathological states has remained
elusive. The immediate-early gene c-fos and phosphorylated ERK1/2 (pERK1/2) are considered reliable indicators for the
neuronal activation status and it permits a comprehensive and large-scale observation of nociceptive neuronal activity along
the ascending pain pathways subjected to tissue injury. In the present study, we systemically demonstrated that peripheral
injury in PKG-Ifl/fl mice produced a significant upregulation of c-Fos or pERK1/2 over from the periphery to the cortex along
the pain pathways, including dorsal root ganglion, spinal dorsal horn, ventral posterolateral thalamus, primary somatosensory
hindlimb cortex, anterior cingulate cortex, basolateral amygdala, periaqueductal gray, and parabrachial nucleus. In contrast,
very few cells in the above regions showed c-Fos or pERK1/2 induction in nociceptor-specific knockout mice lacking PKG-I
(SNS-PKG-I/ mice). Our results indicate that PKG-I expressed in nociceptors is not only a key determinant of dorsal root
ganglion hyperexcitability and spinal synaptic plasticity but also an important modulator of cortical neuronal activity in
pathological pain states and represent what we believe to be novel targets in the periphery for pain therapeutics.
University of Heidelberg.
Vijayan
V
Gangadharan
Fourth Military Medical University.
Xu
X
Wang
Ceng
C
Luo
D000818:Animals; D062965:Cyclic GMP-Dependent Protein Kinase Type I / Q000378:metabolism*; D005727:Ganglia, Spinal / Q000378:metabolism*; D006930:Hyperalgesia / Q000378:metabolism*; D008822:Mice, Transgenic; D009473:Neuronal Plasticity / Q000235:genetics / Q000502:physiology; D009475:Neurons, Afferent / Q000378:metabolism; D009619:Nociceptors / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
D062965:Cyclic GMP-Dependent Protein Kinase Type I