CaMKII Controls Whether Touch Is Painful. J Neurosci 2015 Oct 21;35(42):14086-102
Date
10/23/2015Pubmed ID
26490852Pubmed Central ID
PMC4683679DOI
10.1523/JNEUROSCI.1969-15.2015Scopus ID
2-s2.0-84944929761 (requires institutional sign-in at Scopus site) 25 CitationsAbstract
UNLABELLED: 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.
Author List
Yu H, Pan B, Weyer A, Wu HE, Meng J, Fischer G, Vilceanu D, Light AR, Stucky C, Rice FL, Hudmon A, Hogan QAuthors
Cheryl L. Stucky PhD Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of WisconsinHongwei Yu MD Professor in the Anesthesiology department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AnimalsCalcium-Calmodulin-Dependent Protein Kinase Type 2
Dependovirus
Disease Models, Animal
Enzyme Inhibitors
Excitatory Postsynaptic Potentials
Ganglia, Spinal
Green Fluorescent Proteins
Hyperalgesia
Male
Mechanoreceptors
Mice
Mice, Inbred C57BL
Motor Activity
Nerve Tissue Proteins
Nociceptors
Pain
Pain Threshold
Peripheral Nervous System Diseases
Rats
Rats, Sprague-Dawley
Sensory Deprivation
Signal Transduction
Skin
Touch
