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CaMKII Controls Whether Touch Is Painful.

Abstract
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.
SIGNIFICANCE STATEMENT:
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.
AuthorsHongwei Yu, Bin Pan, Andy Weyer, Hsiang-En Wu, Jingwei Meng, Gregory Fischer, Daniel Vilceanu, Alan R Light, Cheryl Stucky, Frank L Rice, Andy Hudmon, Quinn Hogan
JournalThe Journal of neuroscience : the official journal of the Society for Neuroscience (J Neurosci) Vol. 35 Issue 42 Pg. 14086-102 (Oct 21 2015) ISSN: 1529-2401 [Electronic] United States
PMID26490852 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
CopyrightCopyright © 2015 the authors 0270-6474/15/3514086-17$15.00/0.
Chemical References
  • Enzyme Inhibitors
  • Nerve Tissue Proteins
  • enhanced green fluorescent protein
  • Green Fluorescent Proteins
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2
Topics
  • Animals
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 (genetics, metabolism)
  • Dependovirus (genetics)
  • Disease Models, Animal
  • Enzyme Inhibitors (pharmacology)
  • Excitatory Postsynaptic Potentials (drug effects, genetics)
  • Ganglia, Spinal (cytology)
  • Green Fluorescent Proteins (genetics, metabolism)
  • Hyperalgesia (physiopathology)
  • Male
  • Mechanoreceptors (drug effects, physiology)
  • Mice
  • Mice, Inbred C57BL
  • Motor Activity (genetics)
  • Nerve Tissue Proteins (metabolism)
  • Nociceptors (physiology)
  • Pain (etiology, physiopathology)
  • Pain Threshold (physiology)
  • Peripheral Nervous System Diseases (complications)
  • Rats
  • Rats, Sprague-Dawley
  • Sensory Deprivation (physiology)
  • Signal Transduction (drug effects, physiology)
  • Skin (innervation)
  • Touch (genetics)

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