The Journal of Neuroscience, August 6, 2008, 28(32):7936-7944; doi:10.1523/JNEUROSCI.1259-08.2008
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Neurobiology of Disease
Innocuous, Not Noxious, Input Activates PKC
Interneurons of the Spinal Dorsal Horn via Myelinated Afferent Fibers
Simona Neumann,1,2
Joao M. Braz,1,2
Kate Skinner,1,2
Ida J. Llewellyn-Smith,3 and
Allan I. Basbaum1,2
Departments of 1Anatomy and 2Physiology and W. M. Keck Foundation Center for Integrative Neuroscience, University of California, San Francisco, San Francisco, California 94158, and 3Cardiovascular Medicine and Center for Neuroscience, Flinders University, Bedford Park, South Australia 5042, Australia
Correspondence should be addressed to Simona Neumann, Department of Anatomy, University California, San Francisco, Rock Hall, Mission Bay, 1550 4th Street, San Francisco, CA 94158. Email: neumann{at}phy.ucsf.edu
Protein kinase C 
(PKC), which is concentrated in interneurons of the inner part of lamina II of the dorsal horn, has been implicated in injury-induced allodynia, a condition wherein pain is produced by innocuous stimuli. Although it is generally assumed that these interneurons receive input from the nonpeptidergic, IB4-positive subset of nociceptors, the fact that PKC cells do not express Fos in response to noxious stimulation suggests otherwise. Here, we demonstrate that the terminal field of the nonpeptidergic population of nociceptors, in fact, lies dorsal to that of PKC interneurons. There was also no overlap between the PKC-expressing interneurons and the transganglionic tracer wheat germ agglutinin which, after sciatic nerve injection, labels all unmyelinated nociceptors. However, transganglionic transport of the β-subunit of cholera toxin, which marks the medium-diameter and large-diameter myelinated afferents that transmit non-noxious information, revealed extensive overlap with the layer of PKC interneurons. Furthermore, expression of a transneuronal tracer in myelinated afferents resulted in labeling of PKC interneurons. Light and electron microscopic double labeling further showed that the VGLUT1 subtype of vesicular glutamate transmitter, which is expressed in myelinated afferents, marks synapses that are presynaptic to the PKC interneurons. Finally, we demonstrate that a continuous non-noxious input, generated by walking on a rotarod, induces Fos in the PKC interneurons. These results establish that PKC interneurons are activated by myelinated afferents that respond to innocuous stimuli, which suggests that injury-induced mechanical allodynia is transmitted through a circuit that involves PKC interneurons and non-nociceptive, VGLUT1-expressing myelinated primary afferents.
Key words: PKC; pain; myelinated terminals; spinal cord; sensory neurons; CTB
Received Jan. 2, 2008;
revised June 20, 2008;
accepted June 23, 2008.
Correspondence should be addressed to Simona Neumann, Department of Anatomy, University California, San Francisco, Rock Hall, Mission Bay, 1550 4th Street, San Francisco, CA 94158. Email: neumann{at}phy.ucsf.edu
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