CaMKII Controls Whether Touch Is Painful.
The sensation of touch is initiated when fast conducting low-threshold mechanoreceptors (Aβ-LTMRs) generate impulses at their terminals in the skin. Plasticity in this system is evident in the process of adaption, in which a period of diminished sensitivity follows prior stimulation. CaMKII is an ideal candidate for mediating activity-dependent plasticity in touch because it shifts into an enhanced activation state after neuronal depolarizations and can thereby reflect past firing history. Here we show that sensory neuron CaMKII autophosphorylation encodes the level of Aβ-LTMR activity in rat models of sensory deprivation (whisker clipping, tail suspension, casting). Blockade of CaMKII signaling limits normal adaptation of action potential generation in Aβ-LTMRs in excised skin. CaMKII activity is also required for natural filtering of impulse trains as they travel through the sensory neuron T-junction in the DRG. Blockade of CaMKII selectively in presynaptic Aβ-LTMRs removes dorsal horn inhibition that otherwise prevents Aβ-LTMR input from activating nociceptive lamina I neurons. Together, these consequences of reduced CaMKII function in Aβ-LTMRs cause low-intensity mechanical stimulation to produce pain behavior. We conclude that, without normal sensory activity to maintain adequate levels of CaMKII function, the touch pathway shifts into a pain system. In the clinical setting, sensory disuse may be a critical factor that enhances and prolongs chronic pain initiated by other conditions.


CONCLUSIONS
The sensation of touch is served by specialized sensory neurons termed low-threshold mechanoreceptors (LTMRs). We examined the role of CaMKII in regulating the function of these neurons. Loss of CaMKII function, such as occurred in rats during sensory deprivation, elevated the generation and propagation of impulses by LTMRs, and altered the spinal cord circuitry in such a way that low-threshold mechanical stimuli produced pain behavior. Because limbs are protected from use during a painful condition, this sensitization of LTMRs may perpetuate pain and prevent functional rehabilitation.
Department of Anesthesiology and.
Hongwei
H
Yu
Department of Anesthesiology and.
Bin
B
Pan
Department of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin 53226.
Andy
http://orcid.org/0000-0003-4485-9530
A
Weyer
Department of Anesthesiology and.
Hsiang-En
HE
Wu
Department of Biochemistry and Molecular Biology, Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, Indiana 46202.
Jingwei
J
Meng
Department of Anesthesiology and.
Gregory
G
Fischer
Department of Anesthesiology and.
Daniel
http://orcid.org/0000-0001-7849-7449
D
Vilceanu
Departments of Anesthesiology, and Neurobiology and Anatomy, University of Utah School of Medicine, Salt Lake City, Utah 84132.
Alan R
AR
Light
Department of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin 53226.
Cheryl
C
Stucky
Integrated Tissue Dynamics LLC, Rensselaer, New York 12144 and Department of Biomedical Sciences, State University of New York at Albany, Albany, New York 12222, and.
Frank L
FL
Rice
Department of Biochemistry and Molecular Biology, Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, Indiana 46202.
Andy
A
Hudmon
Department of Anesthesiology and Zablocki Veterans Administration Medical Center, Milwaukee, Wisconsin 53295 qhogan@mcw.edu.
Quinn
Q
Hogan
D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics / Q000378:metabolism*; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D005727:Ganglia, Spinal / Q000166:cytology; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006930:Hyperalgesia / Q000503:physiopathology; D008297:Male; D008465:Mechanoreceptors / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009619:Nociceptors / Q000502:physiology*; D010146:Pain / Q000209:etiology / Q000503:physiopathology*; D017288:Pain Threshold / Q000502:physiology*; D010523:Peripheral Nervous System Diseases / Q000150:complications; D051381:Rats; D017207:Rats, Sprague-Dawley; D012683:Sensory Deprivation / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D012867:Skin / Q000294:innervation; D014110:Touch / Q000235:genetics*
D004791:Enzyme Inhibitors; D009419:Nerve Tissue Proteins; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2
CaMKII; DRG; adaptation; mechanosensation; pain; sensory neuron